associate editor: markku koulu role of...

1521-0081/68/1/168–241$25.00 http://dx.doi.org/10.1124/pr.115.011411PHARMACOLOGICAL REVIEWS Pharmacol Rev 68:168–241, January 2016Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics

ASSOCIATE EDITOR: MARKKU KOULU

Role of Cytochrome P450 2C8 in Drug Metabolism andInteractions

Janne T. Backman, Anne M. Filppula, Mikko Niemi, and Pertti J. Neuvonen

Department of Clinical Pharmacology, University of Helsinki (J.T.B., A.M.F., M.N., P.J.N.), and Helsinki University Hospital, Helsinki,Finland (J.T.B., M.N., P.J.N.)

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169II. Basic Characteristics of Cytochrome P450 2C8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170

A. Genomic Organization and Transcriptional Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170B. Protein Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171C. Expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172

III. Substrates of Cytochrome P450 2C8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173A. Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173

1. Anticancer Agents.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1732. Antidiabetic Agents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1833. Antimalarial Agents.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1834. Lipid-lowering Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1845. Other Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1846. Glucuronide Metabolites.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186

B. Endogenous and Natural Compounds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187IV. Pharmacogenetics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187

A. Population Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187B. Functional Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191C. Effects on Drug Metabolism in Humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192

V. In Vitro Inhibition and Induction of Cytochrome P450 2C8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193A. Reversible Inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193

1. Drugs That Act as Inhibitors of Cytochrome P450 2C8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1932. Natural Compounds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210

B. Metabolism-dependent Inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210C. Induction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210

VI. Clinical Drug Interactions Mediated via Cytochrome P450 2C8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212A. General Aspects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212B. Gemfibrozil as Prototypical Inhibitor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214

1. In Vitro Versus In Vivo.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2142. Gemfibrozil Dose Versus CYP2C8 Inhibition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2163. Onset and Duration of CYP2C8 Inhibition by Gemfibrozil. . . . . . . . . . . . . . . . . . . . . . . . . . . . 2164. Quantification of CYP2C8-Mediated Drug Interactions in Humans. . . . . . . . . . . . . . . . . . . 216

C. Inhibition-Mediated Drug Interactions and Their Clinical Significance . . . . . . . . . . . . . . . . . . 2171. Repaglinide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2172. Other Oral Antidiabetic Drugs.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2183. Amodiaquine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2194. Statins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2195. Anticancer Drugs.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220

This work was supported by grants from the Academy of Finland [Grant decision 278123, 2014], the Helsinki University Central HospitalResearch Fund, and the Sigrid Juselius Foundation (Helsinki, Finland).

Address correspondence to: Prof. Janne T. Backman, Department of Clinical Pharmacology, University of Helsinki and HelsinkiUniversity Hospital, P.O. Box 705, FI-00029 HUS, Finland. E-mail: [email protected]

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6. Antiviral Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2217. Antiasthmatic Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2218. Other Substrate or Inhibitor Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221

D. Induction-Mediated Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2221. Rifampin (Rifampicin). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222

VII. Points to Consider When Investigating Cytochrome P450 2C8-Mediated DrugMetabolism and Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222A. In Vitro . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222

1. General Aspects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2222. Assessment of CYP2C8 Activity In Vitro. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2233. In Vitro Methods to Estimate the Contribution of CYP2C8 in the Metabolism

of a Drug. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224B. In Vivo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224

1. General Aspects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2242. In Vivo Cytochrome P450 2C8 Probe Substrates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2263. In Vivo Cytochrome P450 2C8 Probe Inhibitors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226

VIII. Conclusions and Future Prospects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227Acknowledgments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228

Abstract——During the last 10-15 years, cytochromeP450 (CYP) 2C8 has emerged as an important drug-metabolizing enzyme. CYP2C8 is highly expressed inhuman liver and is known to metabolize more than 100drugs. CYP2C8 substrate drugs include amodiaquine,cerivastatin, dasabuvir, enzalutamide, imatinib,loperamide, montelukast, paclitaxel, pioglitazone,repaglinide, and rosiglitazone, and the number isincreasing. Similarly, many drugs have been identifiedasCYP2C8 inhibitors or inducers. In vivo, already a smalldose of gemfibrozil, i.e., 10% of its therapeutic dose, is astrong, irreversible inhibitor of CYP2C8. Interestingly,recent findings indicate that the acyl-b-glucuronidesof gemfibrozil and clopidogrel cause metabolism-dependent inactivation of CYP2C8, leading to a strongpotential for drug interactions. Also several other

glucuronide metabolites interact with CYP2C8 assubstrates or inhibitors, suggesting that an interplaybetween CYP2C8 and glucuronides is common. Lack offully selective and safe probe substrates, inhibitors,and inducers challenges execution and interpretationof drug-drug interaction studies in humans. Apart fromdrug-drug interactions, some CYP2C8 genetic variantsare associated with altered CYP2C8 activity and exhibitsignificant interethnic frequency differences. Herein,wereviewthecurrentknowledgeonsubstrates, inhibitors,inducers, and pharmacogenetics of CYP2C8, as well asits role in clinically relevant drug interactions. Inaddition, implications for selection of CYP2C8 markerand perpetrator drugs to investigate CYP2C8-mediateddrug metabolism and interactions in preclinical andclinical studies are discussed.

I. Introduction

Cytochrome P450 (CYP) 2C8 accounts for approxi-mately 6–7% of the total hepatic CYP content (RowlandYeo et al., 2004; Inoue et al., 2006; Rostami-Hodjegan andTucker, 2007; Achour et al., 2014). The importance ofCYP2C8 causing variation in drug response via drug-druginteractions and pharmacogenetic polymorphisms hasbeen recognized only for the last 10–15 years. In thebeginning of the millennium, the pharmacokinetic drug-drug interaction between the fibric acid derivative gemfi-brozil and the 3-hydroxy-3-methylglutaryl-coenzyme A

(HMG-CoA) reductase inhibitor cerivastatin, a CYP2C8substrate, resulting in rhabdomyolysis cases and fatalitiesbrought attention to the importance of CYP2C8 in drugmetabolism (Backman et al., 2002; Staffa et al., 2002;Wang et al., 2002; Chang et al., 2004; Huang et al., 2008).The event was the onset of a broadening scientific in-terest in CYP2C8, promptly convincing drug regulatoryauthorities to acknowledge CYP2C8 as one of the majordrug-metabolizing CYP enzymes.

Drugs that were introduced into clinical use beforethe role of CYP2C8 was recognized may have deficient

ABBREVIATIONS: AUC, area under the plasma concentration-time curve; C/EBPa, CCAAT/enhancer-binding protein a; CAR,constitutive androstane receptor; CITCO, [6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime;CLint, intrinsic clearance; Cmax, peak concentration; CYP, cytochrome P450; EMA, European Medicines Agency; FDA, Food and DrugAdministration; GR, glucocorticoid receptor; HLM, human liver microsomes; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; HNF,hepatic nuclear factor; I, inhibitor concentration; Ki, reversible inhibition constant; KI, inhibitor concentration supporting half of themaximal rate of enzyme inactivation; kinact, maximal rate of inactivation; Km, Michaelis-Menten constant; MRL-C, 2-[[5,7-dipropyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy]-2-methylpropanoic acid; mRNA, messenger ribonucleic acid; OAT, organic anion transporter;OATP, organic anion-transporting polypeptide; PPAR, peroxisome proliferator activated receptor; PXR, pregnane X receptor; ROR, retinoicacid-related orphan receptors; SIFT, sorting intolerant from tolerant; SNV, single nucleotide variation; t1/2, elimination half-life; tmax, timeto peak concentration; UGT, uridine-59-diphosphoglucuronosyltransferase; VDR, vitamin D receptor.

Role of CYP2C8 in Drug Metabolism and Interactions 169

or incorrect product information regarding their in-teraction potential (Neuvonen, 2012). One example isthe leukotriene receptor antagonist montelukast.Early preclinical studies concluded that CYP2C9 andCYP3A4 are themost important enzymes involved in itsmetabolism, whereas the role of CYP2C8 was notevaluated (Chiba et al., 1997). In interaction studiesperformedmore than a decade later, the strong CYP2C8inhibitor gemfibrozil increased the plasma exposureto montelukast almost fivefold, whereas the strongCYP3A4 inhibitor itraconazole had no significant effecton its pharmacokinetics (Karonen et al., 2010, 2012).The clinical findings were corroborated by in vitro data,showing that CYP2C8 is the main enzyme involved inthe oxidative metabolism of montelukast (Filppulaet al., 2011; VandenBrink et al., 2011).The large, trifurcated active site cavity of CYP2C8 is

able to accommodate substrates of different shapes andsizes (Schoch et al., 2008). Today, CYP2C8 is known toparticipate in the metabolism of more than 100 drugs,including amodiaquine, cerivastatin, dasabuvir, enzalu-tamide, imatinib, loperamide, montelukast, paclitaxel,pioglitazone, repaglinide, and rosiglitazone. The num-ber of drugs that are identified as CYP2C8 substratesor inhibitors, as well as CYP2C8-mediated drug-druginteractions is continuously increasing. The strongCYP2C8 inhibition by gemfibrozil observed in vivo isdue to its acyl-b-glucuronide metabolite, which is apotent mechanism-based inhibitor of CYP2C8 (Ogilvieet al., 2006). Also other glucuronidemetabolites of drugswere recently found to interact with CYP2C8 either assubstrates or inhibitors. For instance, the acyl-b-D-glucuronide metabolite of clopidogrel is a metabolism-dependent inhibitor of CYP2C8, causing more than afivefold increase in the plasma exposure to repaglinidein healthy subjects (Tornio et al., 2014). In anotherrecent in vitro study, CYP2C8 metabolized the glucu-ronide metabolite of desloratadine to its pharmacolog-ically active 3-hydroxydesloratadine metabolite (Kazmiet al., 2015). These and other data suggest that aninterplay between CYP2C8 and glucuronide metabo-lites may be more a rule than an exception.There are several common nonsynonymous varia-

tions in the CYP2C8 gene (Daily and Aquilante, 2009;Aquilante et al., 2013b). For example, the CYP2C8*3allele has been associated with decreased metabolismof several substrates, e.g., paclitaxel, in vitro (Dai et al.,2001). In contrast, clinical data indicate that theCYP2C8*3allele is often associated with increased metabolism ofCYP2C8 substrates, such as repaglinide (Niemi et al.,2003c). Thus, although complete lack of function variantsin CYP2C8 are rare, the possible substrate dependencyof the functional consequences of the common CYP2C8variants and their potential clinical significance haveraiseda lot of interest towardCYP2C8pharmacogenetics.The structural properties, regulation of expression,

pharmacogenetics, substrates, inhibitors, and physiologic

roles of CYP2C8 have been thoroughly examined anddiscussed in several previous reviews (Kirchheiner et al.,2005; Totah and Rettie, 2005; Garcia-Martin et al., 2006;Gil and Gil Berglund, 2007; Agundez et al., 2009; ChenandGoldstein, 2009;Daily andAquilante, 2009; Lai et al.,2009; Aquilante et al., 2013b; Fleming, 2014; Xiaopinget al., 2013). Thus, the reader will be directed to theseearlier works for some previously known aspects relatedto CYP2C8. Herein, our intention is to review and updatethe current knowledge on substrates, inhibitors, in-ducers, and pharmacogenetics of CYP2C8, as well as itsrole in clinically relevant drug interactions. In addition,implications for selection of CYP2C8 marker and perpe-trator drugs to investigate CYP2C8-mediated drug me-tabolism and interactions in preclinical and clinicalstudies are discussed.

II. Basic Characteristics of Cytochrome P450 2C8

A. Genomic Organization and Transcriptional Regulation

The CYP2C8 enzyme is encoded by theCYP2C8 gene,which is located on the chromosome 10q24 in the 2Cgene cluster centromere-2C18-2C19-2C9-2C8-telomerein close proximity of the CYP2C9 gene (Fig. 1; Grayet al., 1995; Klose et al., 1999). CYP2C8 is the smallestof the human CYP2C genes; it spans a 31-kb region andcontains 9 exons (Klose et al., 1999; Lai et al., 2009). Itshares 74% sequence homology with CYP2C9 (Dailyand Aquilante, 2009).

The transcriptional regulation of CYP2C8 is mediatedvia several transcriptional factors and distinct nuclearreceptors that can activate the respective responsiveelements within the 59-flanking promoter region of thegene (Ferguson et al., 2005; Johnson and Stout, 2005;Kojima et al., 2007; Chen and Goldstein, 2009). Suchfactors/receptors include the constitutive androstane re-ceptor (CAR), pregnane X receptor (PXR), vitamin Dreceptor (VDR), glucocorticoid receptor (GR), hepaticnuclear factor-4a (HNF4a), HNF3g, CCAAT/enhancer-binding protein a (C/EBPa), and retinoic acid-relatedorphan receptors (RORs) (Fig. 1; Ferguson et al., 2005;Chen and Goldstein, 2009; Rana et al., 2010; Aquilanteet al., 2013b). Although HNF4a, HNF3g, C/EBPa, andRORs seem to mainly regulate the constitutive expressionof CYP2C genes in liver, the other receptors are moreimportant to thexenobiotic-mediated inductionofCYP2C8expression, as described in more detail in section V.C.

After activation by endo- or xenobiotics, CAR, PXR,and VDR form heterodimers with the retinoid Xreceptor, whereas GR forms homodimers (Chen andGoldstein, 2009). These dimers are thereafter recog-nized by specific response elements within the CYP2C8promoter. By using in vitro gel shift assays, responsiveelements/motifs within the CYP2C8 promoter regionshave been identified for CAR, PXR, and GR (Gerbal-Chaloin et al., 2002; Ferguson et al., 2005; Chen andGoldstein, 2009).

170 Backman et al.

After activation, the orphan nuclear receptor HNF4abinds as a homodimer to a DR1 type element and alsoto the Hep-G2 specific P450 factor-1 motif (Venepallyet al., 1992), whereas HNF3g binds to DNA as amonomer (Bort et al., 2004). At least two Hep-G2specific P450 factor-1 motifs and several putativeHNF3g binding sites have been identified within thepromoter of CYP2C8 (Bort et al., 2004; Ferguson et al.,2005; Chen and Goldstein, 2009). RORs are constitu-tively active orphan nuclear receptors, which havenatural ligands, such as all-trans-retinoic acid thatcan influence their activity. Also RORs seem to beinvolved in the constitutive regulation of CYP2C8,and at least two ROR responsive elements have beenidentified in the gene promoter (Chen et al., 2009).Transcriptional regulation of CYP2C8 has been re-viewed thoroughly by Chen and Goldstein (2009).

B. Protein Structure

The crystal structure of CYP2C8was resolved in 2004(Schoch et al., 2004). A single CYP2C8 crystal dif-fracted to 2.7 Å and had the molecular weight approx-imated to 54 kDa. Interestingly, CYP2C8 crystallized asa symmetric dimer formed by interactions between thehelix F to G regions of the two monomers. Two palmiticacid molecules were bound in the dimer interface,stabilizing the dimer. Thus, the two fatty acids mayform a peripheral binding site, which may affect thestructural dynamics of the active site and influencereactions catalyzed by CYP2C8. The active site volumeof CYP2C8 was estimated to 1,438 Å3 (Schoch et al.,

2004), which is similar to that of CYP3A4 (1,386 Å3)but larger than those of CYP1A2 (375 Å3), CYP2A6(260 Å3), CYP2C9 (;470 Å3), CYP2D6 (;540 Å3), andCYP2E1 (190 Å3) (Williams et al., 2003; Yano et al.,2004; Rowland et al., 2006; Sansen et al., 2007;Porubsky et al., 2008). Although CYP3A4 has a uni-formly distributed active site cavity, that of CYP2C8 istrifurcated, resembling a T or Y shape (Schoch et al.,2008). The bottom branch of the cavity provides accessto the heme, and the two other terminate in solvent andsubstrate access channels that exit the active site cavityon either side of the helix B-C loop.

In the X-ray crystallography study, the N-terminalanchor domains of both CYP2C8 molecules were lo-cated on the same side of the dimer, indicating anorientation compatible with membrane binding (Schochet al., 2004). The proximal surfaces of each protein wereroughly parallel, suggesting that they are accessible forinteraction with the membrane-bound CYP oxidoreduc-tase. Another study demonstrated that the dimericstructure observed in the crystal structure of CYP2C8may also be present inmembrane-bound native CYP2C8(Hu et al., 2010). The signal anchor/linker regions ofnative CYP2C8 formed a second dimerization interface,and it was suggested that this interaction is requiredfor the formation of the dimer of the native protein.Although direct evidence for a functional significanceof the dimerization is lacking, such interactionshave been shown to affect activities of other CYPs andmembrane proteins in the endoplasmic reticulum (Huet al., 2010).

Fig. 1. The CYP2C8 gene is located to the CYP2C gene cluster on chromosome 10. C/EBPa, CCAAT/enhancer-binding protein a; CAR, constitutiveandrostane receptor; GR, glucocorticoid receptor; HNF, hepatic nuclear factor; PXR, pregnane X receptor; ROR, retinoic acid-related orphan receptor;VDR, vitamin D receptor.


According to the X-ray crystallographic data, theactive site cavity of CYP2C8 is capable of bindingstructurally diverse substrates without major changesin its tertiary structure (Schoch et al., 2008). Ligands ofCYP2C8 may bind to the active site differently, fillingthe cavity either partially or completely or occupying itwith two molecules simultaneously. For instance, mon-telukast, a large anionic molecule with a tripartitestructure, complemented the size and shape of thewhole active-site cavity. The linearly shaped troglita-zone molecule occupied the upper portion of the cavity,leaving a significant part of the cavity empty, whereastwomolecules of 9-cis-retinoic acid were simultaneouslypresent in the substrate-binding cavity of CYP2C8(Schoch et al., 2008). The interactions between CYP2C8and its substrates were predominantly hydrophobic.In addition, the distal region of the CYP2C8 active

site cavity contains a number of polar amino acid sidechains and exposed peptide backbone hydrogen bonddonors and acceptors (Schoch et al., 2008). Accordingly,for example, the residues Ser-100, Ser-103, Asn-204,Asn-217, and Arg-241 form hydrogen bonds involved inthe binding of the CYP2C8 substrates retinoic acid,troglitazone and montelukast. Of note, a pronouncedside chain movement was observed in crystallizedcomplexes with troglitazone and retinoic acid, whereArg-241was reoriented to the inside of the cavity, whereit could provide a strong, charge-stabilized hydrogenbond with the substrate. Interestingly, according tocomputational docking simulations, the glucuronidemoieties of gemfibrozil 1-O-b glucuronide and clopidog-rel acyl 1-b-D-glucuronide are oriented toward the samehydrophilic area in the active site close to helix B9,

where Ser-100 and Ser-103 reside (Fig. 2; Baer et al.,2009; Tornio et al., 2014).

Although the large active site of CYP2C8 anddiversity of its substrates (section III) may complicatethe use of a general pharmacophore model, analysis ofeight CYP2C8 substrates showed that the majority ofthese compounds contained a terminal anionic or polargroup ;13 Å from the oxidation site, and one or twosecondary polar moieties ;4.5 Å and ;8.5 Å from theoxidation site (Melet et al., 2004). The pharmacophoremodel and previously reported homology models forCYP2C8 have been comprehensively reviewed by Laiand colleagues (2009).

C. Expression

According tometa-analyses, themean hepatic CYP2C8concentration approximates to 22–24 pmol/mg and14 pmol/mg in adult Caucasian and Japanese livers,respectively (Rowland Yeo et al., 2004; Inoue et al.,2006; Rostami-Hodjegan and Tucker, 2007; Achouret al., 2014). The interindividual variability of CYP2C8protein expression in liver is high, with coefficients ofvariation of 68–95%. The protein expression levelof CYP2C8 seems to be highly correlated with bothits enzyme activity and messenger ribonucleic acid(mRNA) expression level (Ohtsuki et al., 2012).

Hepatic CYP2C8 mRNA and protein are expressedearly in the prenatal development and reaches adultlevels already in early childhood (Treluyer et al., 1997;Blanco et al., 2000; Naraharisetti et al., 2010; Cizkovaet al., 2014; Johansson et al., 2014). CYP2C8 seems to bethe predominant CYP2C isoform in fetal livers (Hak-kola et al., 1994; Nishimura et al., 2003; Johansson

Fig. 2. Stereoimage of three independent docking simulations of the interaction between clopidogrel acyl 1-b-D-glucuronide and the active site ofCYP2C8. Clopidogrel acyl-b-D-glucuronide is rendered with gray sticks depicting carbon atoms. The distance between clopidogrel acyl-b-D-glucuronidethiophene ring carbon and heme iron is indicated by a green line. Other atoms of the clopidogrel acyl-b-D-glucuronide molecule are colored red foroxygen, blue for nitrogen, yellow for sulfur, and green for chlorine.

172 Backman et al.

et al., 2014). In a recent study, CYP2C8 mRNA wasexpressed in all fetal tissues studied (adrenal, kidney,liver, and lung tissue), whereas CYP2C9 mRNA wasrestricted to the liver (Johansson et al., 2014). Anotherstudy detected CYP2C8, CYP2C9, and CYP2C19 pro-tein in fetal liver, intestine, and kidney (Cizkova et al.,2014). One explanation for the role of CYP2C8 in thefetus during early pregnancymay be a need for CYP2C8to metabolize endogenous compounds such as retinoicacids and hence protect the fetus from retinoic acid-induced embryotoxicity (Johansson et al., 2014).In adults, CYP2C8 mRNA has been detected in

numerous extrahepatic tissues, including the adrenalgland, arteries, brain, duodenum, heart, kidney, lung,mammary gland, ovary, prostate, retina; testis, anduterus, but not in placenta (Zeldin et al., 1995; Maceet al., 1998; McFayden et al., 1998; Klose et al., 1999;Thum and Borlak, 2000; Nishimura et al., 2003;Delozier et al., 2007; Dutheil et al., 2009; Capozzi et al.,2014). CYP2C8 protein has been detected in heart,hepatocytes, kidney, salivary ducts, small and largeintestine, adrenal cortical cells, and tonsils (Läppleet al., 2003; Enayetallah et al., 2004; Delozier et al.,2007; Cizkova et al., 2014). The expression of CYP2C8and other CYP enzymes has recently been reviewed byShahabi et al. (2014).Analysis of liver samples has recently shown that a

nearly full-length form of CYP2C8 (wild type) and anN-terminal truncated splice variant 3 are expressed inmitochondria (Bajpai et al., 2014). Although the wild-type protein was detected only at low levels in mito-chondria (,25%), variant 3 was primarily targeted tomitochondria and minimally to the endoplasmic re-ticulum. Interestingly, although molecular modelingshowed that both the heme binding pocket and thesubstrate binding cavity were nearly intact in variant3, it was unable to catalyze paclitaxel 6-hydroxylationin human hepatocellular liver carcinoma cells. How-ever, it did metabolize smaller substrates such asarachidonic acid and dibenzylfluorescein. Further-more, the variant generated higher levels of reactiveoxygen species and showed a higher level of mitochon-drial respiratory dysfunction than wild type CYP2C8,suggesting that the mitochondrially targeted variant 3may contribute to oxidative stress in tissues (Bajpaiet al., 2014).In living organisms, CYP enzymes undergo natural

degradation that can be described as a first-order process(Yang et al., 2008). Therefore, the expression level ofthe enzyme is determined by the rate of enzymesynthesis and the degradation half-life of the enzyme.The extent and dose and time dependency of enzymeinduction and inactivation are thus also dependent onthe degradation half-life. Based on clinical studieswith the CYP2C8 inactivator gemfibrozil, the degra-dation (turnover) half-life of CYP2C8 is approximately22 hours (Backman et al., 2009).

III. Substrates of Cytochrome P450 2C8

CYP2C8 participates in the metabolism of numerousdrugs and some endogenous and natural compounds. Itcatalyzes a variety of oxidative reactions, in particularhydroxylations, N-demethylations, and N-deethyla-tions (Tables 1–4). Because of its large, sinuous activesite, CYP2C8 can accommodate substrates of differentsizes and structures. The molecular weight of drugssignificantly metabolized by CYP2C8 (.20%; Table 1)ranges from 206 to 854 g/mol, with amedian of 451 g/mol(Fig. 3).

Most, if not all, of the drugs significantly metabolizedby CYP2C8 are also substrates of other CYP enzymes(Table 1), with about 75% beingmetabolized byCYP3A4and ;30% by CYP2C9. However, the metabolic prod-ucts generated by CYP2C8 and CYP3A4 are oftendifferent. For instance, CYP2C8 metabolizes paclitaxelto 6a-hydroxypaclitaxel, whereas CYP3A4 exclusivelygenerates 39-hydroxypaclitaxel (Rahman et al., 1994),suggesting that compounds that are substrates of bothCYP2C8 and CYP3A4 bind differently to their activesites.

A. Drugs

CYP2C8 is involved in the metabolism of more than100 clinically used drugs (Table 1). Typical substratedrugs of CYP2C8 include anticancer, antidiabetic,antimalarial, and lipid-lowering agents (Fig. 4). In-terestingly, some glucuronide metabolites of drugs in-teract with CYP2C8.

1. Anticancer Agents. The antimicrotubule agentpaclitaxel with a molecular weight of 853.9 g/mol isone of the largest substrates of CYP2C8. In vitro,paclitaxel is primarily metabolized by CYP2C8 to itsmain 6a-hydroxy metabolite and by CYP3A4 to 39-phenyl-hydroxypaclitaxel, and the further metabolismof these metabolites results in the formation of 6a, 39-p-dihydroxypaclitaxel (Cresteil et al., 1994, 2002; Harriset al., 1994; Kumar et al., 1994; Rahman et al., 1994).Paclitaxel 6a-hydroxylation is recommended by drugauthorities as a marker reaction for CYP2C8 acti-vity in vitro (EMA, 2012b; http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm), and it hasbeenwidely used in preclinical studies. In amass balancestudy in patients,metabolites accounted for about 40% ofthe total systemic drug exposure, and the excreted 6a-hydroxypaclitaxel corresponded to almost one-third ofthe administered dose (Walle et al., 1995), suggestingthat ;30–40% of a paclitaxel dose is converted byCYP2C8 to 6a-hydroxy paclitaxel.

Cabazitaxel, a taxane approved in 2010, is alsometabolized by CYP2C8 to a small extent in vitro(FDA, 2010a), whereas there is conflicting data re-garding the role of CYP2C8 in the metabolism ofdocetaxel. One in vitro study demonstrated that


http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm



TABLE 1Drugs that are metabolized by CYP2C8, grouped by the importance of CYP2C8 in their elimination (Major, intermediate, minor)

Substrate Therapeutic Use and/orDrug Class

Metabolic Pathway(s)Catalyzed by CYP2C8

Other CYP EnzymesInvolved in Overall

MetabolismaReferences

Major (.70%)Amodiaquine Antimalarial N-deethylation (CYP1A1, CYP1B1) Li et al., 2002Cerivastatin (acid,

parent)Antihyperlipidemic, HMG-

CoA reductase inhibitor6-hydroxylation (M-23),

demethylation (M-1)CYP3A4 Backman et al., 2002

Daprodustat(GSK1278863)

Antianemic, prolylhydroxylase inhibitor

CYP3A4 Johnson et al., 2014

Dasabuvir (ABT-333) Antiviral, NSB5 inhibitor M1 formation CYP3A4, CYP2D6 FDA, 2014gEnzalutamide Anticancer, antiandrogen Hydroxylation (M6),

N-demethylation (M2)CYP3A4/5 FDA, 2012k; Gibbons et al.,

2015Montelukast Antiasthmatic, LTRA 36-hydroxylation (M6),

25-hydroxylation(M3), M4 formation

CYP3A4, CYP2C9 Karonen et al., 2010;Filppula et al., 2011

Pioglitazone Antidiabetic, PPAR-gagonist

Hydroxylation CYP3A4/5, CYP1A1 Jaakkola et al., 2006c; FDA,2013a

Repaglinide Antidiabetic, meglitinideanalog

M2 and M4 formation CYP3A4 Bidstrup et al., 2003;Kajosaari et al., 2005a

Intermediate (20–70%)9cUAB30 Anticancer, retinoid M1-M5 formation CYP2C9, CYP2C19,

(CYP1A2, CYP2B6)Gorman et al., 2007

Acotiamide (Z-338) Antidyspeptic,acetylcholinesteraseinhibitor

Deisopropylation (M-4) CYP1A1, CYP3A4 Furuta et al., 2004; PMDA,2014

Alitretinoin (9-cis-retinoic acid)

Antipsoriatic, retinoid 4-hydroxylation CYP2C9, CYP3A4,CYP26A1

Marill et al., 2002

Amiodarone Antiarrhythmic N-deethylation CYP3A4, (CYP1A2,CYP2C19, CYP2D6)

Ohyama et al., 2000

Chloroquine Antimalarial N-deethylation CYP3A4/5, (CYP2D6) Kim et al., 2003; Projeanet al., 2003a

(2)(+)-Cisapride Gastroprokinetic, 5-HT4receptor agonist

N-dealkylation, 4-hydroxylation, 2-hydroyxlation

CYP3A4, CYP2B6 Desta et al., 2000, 2001

Compound A ERA Hydroxylation Ma et al., 2004Dabrafenib Anticancer, PKI Hydroxylation CYP3A4/5, (CYP2C9,

CYP2C19)Lawrence et al., 2014;

Suttle et al., 2015Fenretinide Anticancer, retinoid 49-hydroxylation,

49-oxidationCYP3A4/5 Illingworth et al., 2011

R/S-Fluoxetine Antidepressant, SSRI N-demethylation CYP2C9, CYP2D6 Wang et al., 2014bR-Ibuprofen Anti-inflammatory, NSAID 2-hydroxylation,

3-hydroxylationCYP2C9 Hamman et al., 1997;

Tornio et al., 2007;Chang et al., 2008

Imatinib Anticancer, PKI N-demethylation CYP3A4/5 Nebot et al., 2010; Filppulaet al., 2013a,b

Irosustat Anticancer, STS inhibitor M9 and M13 formation CYP2C9, CYP3A4/5,(CYP2E1)

Ventura et al., 2011

Isotretinoin (13-cis-retinoic acid)

Antiacne, retinoid 4-hydroxylation CYP3A4 Marill et al., 2002

Loperamide Antidiarrheal, opioid N-demethylation CYP3A4, CYP2B6, CYP2D6 Kim et al., 2004; Niemiet al., 2006

Olanzapine Antipsychotic N-demethylation CYP1A2, CYP2D6, CYP3A4 Korprasertthaworn et al.,2015

Olodaterol Antiasthmatic, LABA O-demethylation CYP2C9, (CYP3A4) FDA, 2014fPaclitaxel (taxol) Anticancer, taxane 6a-hydroxylation CYP3A4 Cresteil et al., 1994;

Rahman et al., 1994;Walle et al., 1995

Paritaprevir (ABT-450) Antiviral, NS3-4A inhibitor CYP3A4 FDA, 2014gPropanoic acid

dronedaroneDrug metabolite Hydroxylation (M10 and

M11)CYP1A1 Klieber et al., 2014

R483 Antidiabetic, PPAR-gagonist

M1 and M4 formation CYP2C19, CYP3A4,(CYP2C9)

Bogman et al., 2010

Rosiglitazone Antidiabetic, PPAR-gagonist

p-hydroxylation,N-demethylation

CYP2C9 Baldwin et al., 1999

Simvastatin acid Antihyperlipidemic, HMG-CoA reductase inhibitor

Oxidation (M1-M3) CYP3A4/5 Prueksaritanont et al., 2003

Tazarotenic acid Antipsoriatic, drugmetabolite (active)

Sulfoxidation Attar et al., 2003

Tozasertib (MK 0457,VX6, VX 680)

Anticancer, PKI N-demethylation CYP3A4 Ballard et al., 2007

Treprostinil Antihypertensive CYP2C9 FDA, 2009bTroglitazone Antidiabetic, PPAR-g

agonistQuinone metabolite

formationCYP3A4 Yamazaki et al., 1999b

(continued )

174 Backman et al.

TABLE 1—Continued





R/S-Verapamil Antihypertensive, CCB N-dealkylation, N-demethylation, O-demethylation

CYP3A4/5, (CYP2E1) Busse et al., 1995; Tracyet al., 1999

Vidupiprant (AMG 853) Antiasthmatic, PGD2receptor antagonist

t-butyl hydroxylation(M2), cyclopropylhydroxylation (M3)

CYP2J2, CYP3A Foti et al., 2012

Zopiclone Sedative, GABA receptoragonist

N-demethylation, N-oxidation

CYP3A4, CYP2C9 Becquemont et al., 1999;Tornio et al., 2006

Unknown or Minor(;,20%)

5-MeO-DIPT (Foxy) Hallucinogenic N-deisopropylation CYP2D6, CYP1A2,CYP3A4, CYP2C19

Narimatsu et al., 2006

7-Epi-10-deacetyl-paclitaxel

Paclitaxel derivative Hydroxylation CYP3A4 Zhang et al., 2009a

7-Epi-cephalomannine Paclitaxel derivative M-2 formation CYP3A4 Zhang et al., 2009a7-Epi-paclitaxel Paclitaxel epimer M-2 formation CYP3A4 Zhang et al., 2009b10-Aceyldocetaxel Docetaxel derivative 6-hydroxylation CYP3A4 Cresteil et al., 200210-Deacetylpaclitaxel Paclitaxel derivative 6-hydroxylation CYP3A4 Cresteil et al., 200217a-Ethinylestradiol Contraceptive, hormone

derivative2-hydroxylation Wang et al., 2004

17b-Estradiol (estradiol) Hormonal replacementtherapy

2-hydroxylation, 4-hydroxylation

CYP1A1, CYP1B1 Spink et al., 1992

Aminophenazone(aminopyrine)

Analgesic N-demethylation CYP2C19, CYP2B6,CYP2D6

Niwa et al., 1999, 2000

Amitriptyline Antidepressant, TCA N-demethylation CYP3A4/5, CYP2C19 Venkatakrishnan et al.,2001

Anastrozole Anticancer, aromataseInhibitor

Hydroxylation CYP3A4, CYP3A5 Kamdem et al., 2010

Apixaban Antithrombotic, factor Xainhibitor

O-demethylation CYP3A4, CYP1A2,CYP2C9, CYP2C19,CYP2J2

FDA, 2012d

Apremilast Antipsoriatic, PDE4inhibitor

M5 formation CYP3A4, CYP2A6,(CYP1A2, CYP2C9,CYP2E1)

FDA, 2014e

Artelinic acid Antimalarial 3-hydroxylation CYP3A4/5 Grace et al., 1999Atorvastatin (acid,

parent)Antihyperlipidemic, HMG-

CoA reductase inhibitorp-hydroxylation CYP3A4/5 Jacobsen et al., 2000b

Azilsartan Antihypertensive, ARB Decarboxylation (M-I),O-dealkylation (M-II)

CYP2C9, CYP2B6 FDA, 2011c

Bedaquiline Antibiotic, ATP synthaseinhibitor

N-demethylation CYP3A4, CYP2C19 Liu et al., 2014

Brinzolamide Antiglaucoma, carbonicanhydrase inhibitor

CYP3A4, CYP2A6,CYP2B6, CYP2C9

EMA, 2014

Brivaracetam Antiepileptic Hydroxylation CYP2C9, CYP3A4 Whomsley et al., 2007;Nicolas et al., 2012

Buprenorphine Analgesic, opioid N-dealkylation, M1formation

CYP3A4 Moody et al., 2002; Picardet al., 2005; Chang et al.,2006

Buspirone Anxiolytic CYP3A4 Karlsson et al., 2013BYZX Antidementia,

acetylcholinesteraseinhibitor

N-deethylation (M3) CYP3A4 Yu et al., 2013a

BYZX M2 Drug metabolite N-deethylation (M1) CYP3A4 Yu et al., 2013aCabazitaxel Anticancer, taxane RPR 112698 formation CYP3A4/5 FDA, 2010aCaffeine Psychostimulant N-demethylation,

C-8-hydroxylationCYP3A4, CYP1A2, CYP2C9 Kot and Daniel, 2008

Capravirine Antiviral, NNRTI Sulfoxidation (C23),N-oxidation (C26),hydroxylation (C19)

CYP3A4, CYP2C9,CYP2C19

Bu et al., 2006

Carbamazepine Antiepileptic 10,11-epoxidation,3-hydroxylation

CYP3A4 Kerr et al., 1994; Pelkonenet al., 2001

Cephalomannine Paclitaxel derivative 4a-hydroxylation Zhang et al., 2009aCerlapirdine Antidementia, 5-HT6

receptor antagonistDemethylation CYP3A4 Tse et al., 2014

Cilostazol Antithrombotic, PDE3inhibitor

OPC-13217 formation CYP3A4/5, CYP1B1,CYP2C19

Hiratsuka et al., 2007

Cinitapride Gastroprokinetic, 5-HT4receptor agonist

CYP3A4 Robert et al., 2007

E-Clomiphene Ovulation inducer, SERM Deethylation,hydroxylation

CYP3A4/5, CYP2D6 Mürdter et al., 2012

Clozapine Antipsychotic N-demethylation, oxidation CYP1A2,(CYP3A4)

Linnet and Olesen, 1997

(continued )


TABLE 1—Continued





CPI-613 Anticancer,antimitochondrialmetabolism agent

CYP3A4, (CYP2C9,CYP2C19)

Lee et al., 2011

Cyamemazine Antipsychotic N-demethylation CYP1A2, CYP3A4, CYP2C9 Arbus et al., 2007Cyclophosphamide Anticancer, alkylating

agent4-hydroxylation CYP2C9, CYP2A6,

CYP2B6, CYP3A4Chang et al., 1993; Huang

et al., 2000Cyclosporine Immunosuppressant,

calcineurin inhibitorCYP3A4 Karlsson et al., 2013

Dapsone Antimicrobial N-hydroxylation CYP2C9 Winter et al., 2000Diazepam Anxiolytic, benzodiazepine N-demethylation, 3-

hydroxylationCYP2C9, CYP3A4,

CYP2C19Sai et al., 2000

Dibenzylfluorescein Fluorescent CYP probe O-debenzylation CYP3A4, CYP2C19,CYP2C9, CYP3A5,CYP3A7

Miller et al., 2000

Diclofenac Anti-inflammatory, NSAID 49-hydroxylation, 5-hydroxylation

CYP2C9, CYP3A4,CYP2C18/19

Mancy et al., 1999

Diltiazem Antihypertensive, CCB N-demethylation CYP3A4, CYP2C9, CYP2D6 Sutton et al., 1997Docetaxel Anticancer, taxane Baccatin ring hydroxylation CYP3A4 Komoroski et al., 2005Dovitinib Anticancer, PKI CYP1A1/2, CYP2D6,

CYP3A4Kim et al., 2011c

DY-9760e Calmodulin antagonist Imidazole oxidation (M8),N-dealkylation (DY-9836), O-demethylation(M5), phenylhydroxylation (M3)

CYP3A4, CYP2C9,CYP2C19

Tachibana et al., 2005

Eltrombopag Antihemorrhagic, c-mplreceptor agonist

Monooxygenation (J andM6)

CYP1A2 FDA, 2008c

Elzasonan Antidepressant N-demethylation (M4) CYP3A4 Kamel et al., 2013Erlotinib Anticancer, PKI CYP3A4/5, CYP1A2,

CYP1A1, CYP1B1FDA 2004; Ling et al., 2006

Ethanol Alcohol, solvent Acetaldehyde formation CYP2E1, CYP1A2 Hamitouche et al., 2006Etodolac Anti-inflammatory, NSAID 6-hydroxylation, 7-

hydroxylationCYP2C9 Tougou et al., 2004

Evatanepag (CP-533,536) Prostaglandin EP2 receptoragonist

Formation of M3, M4, M20,M22-M6

CYP3A4/5 Prakash et al., 2008

Everolimus Immunosuppressant, PKI Hydroxylation CYP3A4/5 Jacobsen et al., 2001;Picard et al., 2011

Febuxostat Antihyperuricemic, XOinhibitor

Hydroxylation (67M-2) CYP1A2, CYP2C9 Mukoyoshi et al., 2008;FDA, 2009c

Felodipine Antihypertensive, CCB CYP3A4 Karlsson et al., 2013Flutamide Anticancer, antiandrogen Flu-1-G2 formation CYP1A2, CYP3A4, CYP2C9 Kang et al., 2008Fluvastatin (acid, parent) Antihyperlipidemic, HMG-

CoA reductase inhibitor5-hydroxylation CYP2C9, CYP1A1,

CYP2D6, CYP3A4Fischer et al., 1999

Gallopamil Antiarrhythmic, CCB Oxidation CYP3A4, CYP2D6 Suzuki et al., 1999Genistein Anticancer, PKI 39-hydroxylation CYP1A2, CYP2E1 Hu et al., 2003Gliclazide Antidiabetic, sulfonylurea 6b-hydroxylation, 7b-

hydroxylationCYP2C9, CYP2C19 Elliot et al., 2007

Glyburide(glibenclamide)

Antidiabetic, sulfonylurea 4-trans- (M1) and 3-cis-hydroxycyclohexyl (M2b)glyburide formation

CYP3A4, CYP2C9, CYPC19 Zharikova et al., 2009

Halofantrine Antimalarial N-debutylation CYP3A4/5 Baune et al., 1999Ibrolipim (NO-1886) Antihyperlipidemic O-deethylation (M2) CYP3A4 Morioka et al., 2002ID951551 Acotiamide analog Deisopropylation CYP3A4, CYP1A1 Furuta et al., 2004Ifosfamide Anticancer, alkylating

agent4-hydroxylation CYP2C9, CYP2A6,

CYP2B6, CYP3A4Chang et al., 1993; Huang

et al., 2000IN-1130 Anticancer, PKI M1 and M3 formation CYP3A4, CYP2D6,

CYP2C19Kim et al., 2008

K11777 Antiparasitic, cysteineprotease inhibitor

Formation of N-oxide CYP3A4 Jacobsen et al., 2000ab-hydroxy-homoPhe and N-

demethyl metabolitesKarenicetin Anticancer CYP3A4, CYP2D6 Smith et al., 2003L-775,606 Antimigraine, triptan Hydroxylation (M1), N-

dealkylation (M2)CYP3A4 Prueksaritanont et al., 2000

Lansoprazole Antiulcerative, PPI 5-hydroxylation CYP2C19, CYP3A4 Pichard et al., 1995Lapatinib Anticancer, PKI O-dealkylation, N-

dealkylationCYP3A4/5, CYP2C19 FDA, 2007e; Teng et al.,

2010Licofelone Anti-inflammatory, NSAID Hydroxylation (M2 and M4) CYP2C9, CYP2C19,

CYP2D6, CYP2J2,CYP3A4

Albrecht et al., 2008

Lonafarnib Anticancer, FTI Hydroxylation (M4) CYP3A4/5, CYP1A1 Ghosal et al., 2006Macitentan Antihypertensive, ERA Depropylation CYP3A4, CYP2C9,

CYP2C19Sidharta et al., 2015

(continued )

176 Backman et al.

TABLE 1—Continued





Mavoglurant Anti-Parkinson, mGLUR5antagonist

M7 formation CYP3A4, CYP1A1 Walles et al., 2013

Methadone Analgesic, opioid N-demethylation CYP2B6, CYP3A4, CYP2D6 Iribarne et al., 1996; Wangand DeVane, 2003;Chang et al., 2011

Mirodenafil Erectogenic, PDE5inhibitor

N-dealkylation CYP3A4, CYP2D6 Lee et al., 2008

Mirtazapine Antidepressant, NaSSA N-demethylation CYP2D6, CYP1A2, CYP3A4 Störmer et al., 2000Morphine Analgesic, opioid N-demethylation CYP3A4 Projean et al., 2003bMuraglitazar Antidiabetic, PPARa, and g

agonistO-demethylation, O-

dealkylationhydroxylation, N-acetyl-imide metaboliteformation

CYP2C9, CYP2C19,CYP2D6, CYP3A4

Zhang et al., 2007a

(2)(+)-Naftopidil Antihypertensive M1-M5 formation CYP2C9, CYP2C19 Zhu et al., 2014Nalfurafine Antipruritic, opioid Decyclopropylmethylation CYP3A4, CYP2C9,

CYP2C19Ando et al., 2012

Naproxen Anti-inflammatory, NSAID O-demethylation CYP2C9, CYP1A2 Rodrigues et al., 1996,Tracy et al., 1997

Nicotine Psychostimulant 5-hydroxylation CYP2A6, CYP2B6 Yamazaki et al., 1999aNifedipine Antihypertensive, CCB CYP3A4/5 Karlsson et al., 2013Nilotinib Anticancer, PKI CYP3A4, CYP1A1/2,

CYP2J2FDA, 2007c

R/S-Norverapamil Drug metabolite O-demethylation, N-dealkylation

CYP3A4/5 Tracy et al., 1999

Odanacatib Antiosteoporotic, cathepsinK enzyme inhibitor

Methyl hydroxylation (M8) CYP3A4/5 Kassahun et al., 2014

Ombitasvir (ABT-267) Antiviral, NS5A inhibitor CYP3A4, CYP3A5 FDA, 2014kOmeprazole Antiulcerative, PPI 5-hydroxylation CYP2C19, CYP3A4 Karam et al., 1996Pafuramidine maleate

(DB289)Antiparasitic O-demethylation (M1) CYPF4 Wang et al., 2006

Pazopanib Anticancer, PKI Mono-oxygenation CYP3A4, CYP1A2 FDA, 2009dPerospirone Antipsychotic MX 1, 10-11614, CO-UK2,

and CO-UK3 formationCYP3A4, CYP2D6,

(CYP1A1)Mizuno et al., 2003;

Kitamura et al., 2005Perphenazine Antipsychotic N-dealkylation CYP1A2, CYP3A4,

CYP2C19, CYP2D6,(CYP2C18)

Olesen and Linnet, 2000

Phenazone (antipyrine) Analgesic N-demethylation, 3-hydroxylation, 4-hydroxylation

CYP3A4, CYP1A2, CYP2C9 Engel et al., 1996

Phenprocoumon Antithrombotic, VKA S-49-hydroxylation CYP2C9, CYP3A4 Ufer et al., 2004Phenytoin Antiepileptic 4-hydroxylation CYP2C9, CYP2C19 Doecke et al., 1990Piperaquine Antimalarial CYP3A4 Lee et al., 2012cPitavastatin acid Antihyperlipidemic, HMG-

CoA reductase inhibitorCYP2C9 Fujino et al., 2004

Ponatinib Anticancer, PKI CYP3A4, CYP2D6, CYP3A5 FDA, 2012eProgesterone Hormonal replacement

therapyCYP2C19, CYP3A4 Waxman et al., 1991

Propofol Anesthetic 4-hydroxylation CYP2C9, CYP1A2, CYP2B6 Guitton et al., 1998Riociguat Antihypertensive, sGC

stimulatorN-demethylation CYP1A1, CYP3A4, CYP2J2 FDA, 2013b

Rotigotine Anti-Parkinson, dopamineagonist

Desthienylethyl rotigotineformation

CYP1A2, CYP2C9, CYP3A4 FDA, 2007b

Sarizotan Antipsychotic M203, EMD148107, EMD329989, and M364dformation

CYP3A4, CYP2C9, CYP1A2 Gallemann et al., 2010

Selegiline Anti-Parkinson, MAO-Binhibitor

N-demethylation CYP2B6, CYP2C19 Hidestrand et al., 2001,Salonen et al., 2003

Semagacestat Antidementia, g-secretaseinhibitor

Benzylic hydroxylation(M3)

CYP3A4/5 Yi et al., 2010

Seratrodast Antiasthmatic, TXRA 5-methyl hydroxylation, 49-hydroxylation

CYP3A4/5, CYP2C9 Kumar et al., 1997

Sildenafil Erectogenic, PDE5inhibitor

CYP3A4, CYP2C9 Karlsson et al., 2013

Simeprevir (TMC435) Antiviral, proteaseinhibitor

M21 and M2 formation CYP3A4/5, CYP2C19 FDA, 2013h

Sipoglitazar Antidiabetic, PPARaagonist

Hydroxylation (M-II) Nishihara et al., 2012

Sirolimus Immunosuppressant Hydroxylation CYP3A4/5 Jacobsen et al., 2001Sitagliptin Antidiabetic, DPP-4

inhibitorM2 and M5 formation CYP3A4 Vincent et al., 2007

Sulfadiazine Antimicrobial N-hydroxylation CYP2C9 Winter and Unadkat, 2005

(continued )


docetaxel at high concentrations was metabolized byCYP2C8, but no enzyme kinetic parameters weredetermined (Komoroski et al., 2005). An earlierstudy, however, suggested that CYP2C8 is unable toaccommodate docetaxel in its active site because ofthe absence of a side chain in the docetaxel mole-cule (Cresteil et al., 2002). The side chain, which ispresent in the paclitaxel molecule, is required fora correct orientation of it into the active site ofCYP2C8.

The androgen receptor antagonist enzalutamide, in-dicated for treatment of castration-resistant prostatecancer, is mainly metabolized by CYP2C8 and CYP3A4/5 to enzalutamideM6 in vitro (FDA, 2012k). Then,M6 isfurthermetabolized by CYP2C8 to the activemetaboliteN-demethyl enzalutamide (M2), which accounts forapproximately 50% of the total drug exposure inplasma. CYP2C8 seems to be the predominant enzymeinvolved in enzalutamide pharmacokinetics also in vivo(section VI.C.5; Gibbons et al., 2015).

TABLE 1—Continued





Sunitinib Anticancer, PKI N-deethylation CYP3A4, CYP2B6,CYP2C9/19

FDA, 2006b

T-5 Erectogenic, PDE5inhibitor

N-oxidation CYP3A5 Li et al., 2014a

Tacrolimus Immunosuppressant,calcineurin inhibitor

CYP3A4/5 Karlsson et al., 2013

Tamoxifen Anticancer, SERM M-I formation CYP3A4/5, CYP2D6 Desta et al., 2004Tamoxifen N-oxide Drug metabolite Reduction to tamoxifen CYP2A6, CYP1A1, CYP3A4 Parte and Kupfer, 2005Tegafur Anticancer, prodrug 5-hydroxylation CYP1A2, CYP2A6 Komatsu et al., 2000b, 2001Temazepam Sedative, benzodiazepine N-demethylation Yang et al., 1998Terbinafine Antifungal N-demethylation, side

chain oxidationCYP2C9, CYP1A2, CYP3A4 Vickers et al., 1999

Testosterone Hormonal replacementtherapy

CYP3A4/5, CYP2B6 Waxman et al., 1991

Tienilic acid Diuretic 5-hydroxylation CYP2C9 Lopez Garcia et al., 1993;Bonierbale et al., 1999

Tipifarnib Anticancer, FTI CYP3A4, CYP2C19,CYP2A6, CYP2D6,CYP2C9

Perez-Ruixo et al., 2006

R-Tofisopam Anxiolytic M3 formation CYP3A4, CYP2C9,(CYP3A5, CYP2C19)

Cameron et al., 2007

Tolbutamide Antidiabetic, sulfonylurea p-methyl hydroxylation CYP2C9, CYP2C19 Relling et al., 1990;Veronese et al., 1993;Rettie et al., 1994;Komatsu et al., 2000a

Torsemide (torasemide) Diuretic Methyl hydroxylation CYP2C9 Miners et al., 2000; Onget al., 2000

Trabectedin Anticancer N-demethylation CYP3A4, CYP2D6 Vermeir et al., 2009Tretinoin (all-trans-

retinoic acid)Antiacne, retinoid 4-hydroxylation,

18-hydroxylation,5,6-epoxy metaboliteformation

CYP26A1, CYP3A4/5,CYP2B6, CYP1A2,CYP26, CYP2C9

Leo et al., 1989; Nadin andMurray, 1999; Marillet al., 2000; Thatcheret al., 2010

Trimethadione(troxidone)

Antiepileptic N-demethylation CYP2E1, CYP3A4, CYP2C9 Kurata et al., 1998

Vanoxerine Antiarrhythmic, DRI CYP3A4, CYP2E1 Cherstniakova et al., 2001R-Warfarin Antithrombotic, VKA 4-hydroxylation,

7-hydroxylationCYP3A4, CYP1A1,

CYP2C19, CYP1A2Scordo et al., 2002; Kim

et al., 2012Vitamin A (retinol) Anti-acne, retinoid Hydroxylation CYP1A1, CYP1A2,

CYP1B1, CYP2D6,CYP3A4

Leo et al., 1989

Vortioxetine Antidepressant, SMS Sulfoxide (M4a) formation CYP2D6, CYP3A4/5,CYP2C19, CYP2C9,CYP2A6

FDA, 2013j; Chen et al.,2014

Zidovudine Antiviral, NRTI Reduction CYP2C9 Eagling et al., 1994

5-HT, 5-hydroxytryptamine (serotonin); 5-MeO-DIPT, 5-methoxy-N,N-diisopropyltryptamine; 9cUAB30, (2E,4E,6Z,8E)-8-(39,4’-dihydro-1’(2’H)-naphthalen-1’-ylidene)-3,7-dimethyl-2,4,6- octatrienoic acid; ARB, angiotensin II receptor blocker; ATP, adenosine triphosphate; BYZX, [(E)-2-(4-((diethylamino)methyl)benzylidene)-5,6-dimethoxy-2,3-dihydroinden-one];CCB, calcium channel blocker; Compound A, [(+)-(5S,6R,7R)-2-isopropylamino-7-[4-methoxy-2-((2R)-3-methoxy-2-methylpropyl)-5-(3,4-methylenedioxyphenyl) cyclopenteno[1,2-b]pyridine 6-carboxylic acid]; DPP, dipeptidyl peptidase; DRI, dopamine reuptake inhibitor; DY-9760, 3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate; ERA, endothelin receptor antagonist; FTI, farnesyl transferase inhibitor; GABA, g-aminobutyric acid; HMG-CoA,3-hydroxy-3-methylglutaryl-coenzyme A; IN-1130, 3-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)benzamide; K11777, N-methyl-piperazine-Phe-homoPhe-vinylsulfone-phenyl; L-775,606, (1-(3-(5-(1,2, 4-triazol-4-yl)-1H-indol-3-yl)propyl)-4-(2-(3-fluorophenyl)ethyl)piperazine); LABA, long-acting b-adrenoceptor agonist; LTRA,leukotriene receptor antagonist; MAO, monoamine oxidase; mGLUR, metabotropic glutamate receptor; c-mpl, myeloproliferative leukemia; NaSSA, noradrenergic andspecific serotonergic antidepressant; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside analog reverse transcriptase inhibitor; NS, nonstructuralprotein; NSAID, nonsteroidal anti-inflammatory drug; PDE, phosphodiesterase; PGD2, prostaglandin D2; PKI, protein kinase inhibitor; PPAR, peroxisome proliferator-activated receptor; PPI, proton pump inhibitor; sGC, soluble guanylate cyclase; SERM, selective estrogen receptor modulator; SMS, serotonin modulator andstimulator; SSRI, selective serotonin reuptake inhibitor; STS, steroid sulfatase; T-5, methyl 2-(4-aminophenyl)-1-oxo-7-(pyridin-2-ylmethoxy)-4-(3,4,5-trimethox-yphenyl)-1,2-dihydroisoquinoline-3-carboxylate; TCA, tricyclic antidepressant; TXRA, thromboxane A2 receptor antagonist; VKA, vitamin K antagonist; XO, xanthineoxidase.

aThis information is either based on the references given in the table or on data from the UW Metabolism and Transport Drug Interaction Database (DIDB), CopyrightUniversity of Washington 1999-2015 (DIDB Accessed May-September, 2015).

178 Backman et al.

Several protein kinase inhibitors are metabolizedby CYP2C8 to various degrees in vitro (Table 1). Invitro, the majority (60–70%) of dabrafenib, a selectiveBRAF inhibitor, is metabolized by CYP2C8, and asmaller part by CYP3A4 (;25%) and CYP2C9 (#10%)(Lawrence et al., 2014). Recombinant CYP2C8 pro-duced only hydroxydabrafenib, whereas CYP3A4 formedboth hydroxydabrafenib and carboxydabrafenib. How-ever, the in vivo importance of CYP2C8 in dabrafenibpharmacokinetics seems to be quite modest (section VI.C.5; Suttle et al., 2015). Imatinib, the first tyrosinekinase inhibitor approved for clinical use, is metabo-lized by several CYP enzymes in vitro, with CYP2C8and CYP3A4 being the most important ones (Nebotet al., 2010; Filppula et al., 2013a). CYP3A4 is involvedin several metabolic pathways of imatinib, whereas

CYP2C8 only catalyzes the formation of the mainmetabolite, N-demethylimatinib (Table 4; Rochat et al.,2008; Filppula et al., 2013a). The relative roles ofCYP2C8 and CYP3A4 in the in vivo pharmacokineticsof imatinib are complex (section VI.C.5; Filppula et al.,2013b). In vitro, the multitargeted tyrosine kinaseinhibitor ponatinib is mainly metabolized by CYP3A4,followed by CYP2C8, CYP2D6, and CYP3A5. The con-tributions of CYP3A4 and CYP2C8 to the in vivoelimination of ponatinib are estimated to 34% and 19%,respectively (FDA, 2012e). Furthermore, CYP2C8 playsa major role in theN-demethylation of the aurora kinaseinhibitor tozasertib (Table 4; Ballard et al., 2007). Withthe exception of dabrafenib and imatinib, the in vivoimportance of CYP2C8 in the metabolism of proteinkinase inhibitors seems to have been poorly studied.

TABLE 2Glucuronide metabolites that are metabolized by CYP2C8

Substrate Metabolic pathwaycatalyzed by CYP2C8

Other CYP enzymes involvedin overall metabolism References

Clopidogrel acyl 1-b-D-glucuronidea Tornio et al., 2014Desloratadine N-glucuronide 3-hydroxylation Kazmi et al., 2015Diclofenac acyl glucuronide 49-hydroxylation Kumar et al., 2002Estradiol-17b-glucuronide 2-hydroxylation CYP3A7 Delaforge et al., 2005Gemfibrozil 1-O-b glucuronide Benzylic oxidation Ogilvie et al., 2006; Baer et al., 2009Licofelone 1-O-acyl glucuronide (M1) Hydroxylation (M3) Albrecht et al., 2008Lu AA34893 carbamoyl glucuronidea Kazmi et al., 2010MRL-C acyl glucuronide Hydroxylation CYP3A4 Kochansky et al., 2005Sipoglitazar b-1-O-acyl glucuronide O-dealkylation (M-I) Nishihara et al., 2012

MRL-C, 2-[[5,7-dipropyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy]-2-methylpropanoic acid.aThese glucuronides are likely to be substrates of CYP2C8 based on their metabolism-dependent inhibitory effect on CYP2C8.

TABLE 3Natural and endogenous compounds that are metabolized by CYP2C8

Substrate Description Metabolic Pathway(s)Catalyzed by CYP2C8

Other CYP Enzymes Involvedin Overall Metabolisma References

1-Hydroxyl-2,3,5-trimethoxyxanthone Constituent ofHalenia elliptica

M1-M4 formation CYP3A4, CYP1A2,CYP2A6, CYP2B6,CYP2C9, CYP2C19

Feng et al., 2014

7a- and 7b-Hydroxy-D8-THC Marijuana constituent Oxidation CYP3A4, CYP2C9 Watanabe et al., 20078-Prenylnaringenin (flavaprenin) Prenylflavonoid M2 formation CYP2C19 Guo et al., 2006Arachidonic acid Endogenous

compoundCYP2C9, CYP1A2,

CYP2E1, CYP2J2Daikh et al., 1994; Rifkind

et al., 1995; Zeldin et al.,1995; Barbosa-Sicard et al.,2005

Eicosapentaenoic acid Endogenouscompound

CYP2C9/11/23 Barbosa-Sicard et al., 2005

Eupatilin Flavone 4-O-demethylation CYP1A2 Lee et al., 2007R/S-Limonene Terpene CYP2C19, CYP2C9,

CYP3A4Miyazawa et al., 2002

Magnolin Constituent of Shin-i O-demethylation(M1 and M2),hydroxylation (M4)

CYP2C9, CYP2C19,CYP3A4

Kim et al., 2011a

Mesaconitine Alkaloid M1-M2, M7-M9formation

CYP3A4, CYP2C9,CYP2D6

Ye et al., 2011

Nitidine chloride Alkaloid CYP3A4 Li et al., 2014bSilybin (silibinin) Flavonolignan O-demethylation (CYP3A4) Jancova et al., 2007Tanshinol borneol ester Combination of the

natural compoundsdanshensu andborneol

M1-M5 formation (CYP3A4) Liu et al., 2010b

THC, tetrahydrocannabinol.aThis information is either based on the references given in the table or on data from the UW Metabolism and Transport Drug Interaction Database (DIDB), Copyright

University of Washington 1999-2015 (DIDB Accessed May-September, 2015).


TABLE 4CYP2C8-mediated reactions in vitro

Substrate Metabolic Pathway Km Vmax CLinta Test System References

mM pmol/min/pmol(pmol/min/mg)

ml/min/pmol(ml/min/mg)

5-MeO-DIPT (Foxy) N-deisopropylation 291 1.7 0.0058 rCYP2C8 Narimatsu et al., 20067-Epi-10-deacetyl-

paclitaxelHydroxylation 18.0 3.038 0.17 rCYP2C8 Zhang et al., 2009a

7-Epi-cephalomannine M-2 formation 2.6 1.882 0.72 rCYP2C8 Zhang et al., 2009a7-Epi-paclitaxel M-2 formation 1.4 1.409 1.0 rCYP2C8 Zhang et al., 2009b8-prenylnaringenin M2 formation 3.72 4.64 1.3 rCYP2C8 Guo et al., 200617a-ethinylestradiol 2-hydroxylation 12 0.064 0.0053 rCYP2C8 Wang et al., 2004Acotiamide (Z-338) Deisopropylation 152 (12.7) (0.084) rCYP2C8 Furuta et al., 2004

318 (347) (1.19) HLM Furuta et al., 2004Alitretinoin (9-cis-retinoic

acid)4-hydroxylation 7 0.948 0.14 rCYP2C8 Marill et al., 2002

Aminophenazone(aminopyrine)

N-demethylation 5,300 188 0.035 rCYP2C8 Niwa et al., 1999

Amiodarone N-deethylation 8.6 2.3 0.27 rCYP2C8 Ohyama et al., 20005.22 (12.2) (2.3) rCYP2C8 Soyama et al., 2002

Amitriptyline N-demethylation 0.072 rCYP2C8 Venkatakrishnan et al.,2001

Amodiaquine N-deethylation 0.9-1.2 2.6-3.9 2.1-4.4 rCYP2C8 Li et al., 20022.4 (1,462) (610) HLM Li et al., 20020.728 11.2 15 rCYP2C8 Walsky and Obach, 20041.89 (1,480) (780) HLM Walsky and Obach, 20040.81 0.23 0.28 rCYP2C8 Parikh et al., 20071 11 11 rCYP2C8 O’Donnell et al., 20071.95 6.87b 3.5b rCYP2C8 Baer et al., 20091.6 (9,130) (5,700) HLM Perloff et al., 20093.0 5.7b 1.9b rcCYP2C8 Kaspera et al., 2011

3.33-5.17 (1,180-2,770) (220-830) HLM Sjogren et al., 20123.9-7.3 (791-861) (120-200) HLM Yang et al., 2012

1.9 (2,196) (1,200) HLM Misaka et al., 20131.8 (7.3) (4.1) HIM Misaka et al., 2013

58.8 3,234c 55c Hep Kosugi et al., 20140.22-42.44 19.91-1,140c 24-95c Hep Li and Schlicht, 2014

Anastrozole Hydroxylation 86.8 0.00005 ,0.001 rCYP2C8 Kamdem et al., 2010Arachidonic acid Total oxidative

metabolism6.0 4.6d 0.77d rCYP2C8 Barbosa-Sicard et al., 2005

Epoxidation 71 0.078 0.0011 rCYP2C8 Lundblad et al., 2005Atorvastatin (acid, parent) p-hydroxylation 35.9 0.29 0.0081 rCYP2C8 Jacobsen et al., 2000bBedaquiline N-demethylation 13.1 rCYP2C8 Liu et al., 2014Buprenorphine N-dealkylation 12.4 (176.3) (14) rCYP2C8 Picard et al., 2005Buspirone Total oxidative metabolism 0.073 rCYP2C8 Karlsson et al., 2013BYZX N-deethylation (M3) 62.1 0.099e 0.0016e rCYP2C8 Yu et al., 2013aBYZX M2 N-deethylation (M1) 143.2 (0.000370) (,0.001) rCYP2C8 Yu et al., 2013aCaffeine 1-N-demethylation 920 0.014 ,0.001 rCYP2C8 Kot and Daniel, 2008

3-N-demethylation 200 0.016 ,0.001 rCYP2C8 Kot and Daniel, 20087-N-demethylation 3,560 0.172 ,0.001 rCYP2C8 Kot and Daniel, 2008C-8-hydroxylation 3,370 0.319 ,0.001 rCYP2C8 Kot and Daniel, 2008

Carbamazepine 10,11-epoxidation 757 0.669 ,0.001 rCYP2C8 Cazali et al., 2003Cephalomannine 6a-hydroxylation 41.3 5.267 0.13 rCYP2C8 Zhang et al., 2009aCerivastatin (acid, parent) 6-hydroxylation 23 0.22 0.0096 rcCYP2C8 Kaspera et al., 2010

Demethylation 24 0.57 0.024 rcCYP2C8 Kaspera et al., 2010Cerlapirdine Demethylation 3.3 3.4 1.0 rCYP2C8 Tse et al., 2014Chloroquine N-deethylation 430 52.1 0.12 rCYP2C8 Kim et al., 2003

111 8.33 0.075 rCYP2C8 Projean et al., 2003aCilostazol OPC-13217 formation 33.8 0.30 0.089 rCYP2C8 Hiratsuka et al., 2007Cisapride 4-hydroxylation ;5.9 0.71 ;0.12 rCYP2C8 Desta et al., 2000

N-dealkylation ;0.91 0.29 ;0.32 rCYP2C8 Desta et al., 20002-hydroxylation 5.80 0.0267 0.0046 rCYP2C8 Pearce et al., 20014-hydroxylation 3.40 0.289 0.085 rCYP2C8 Pearce et al., 2001N-dealkylation 2.0 0.109 0.055 rCYP2C8 Pearce et al., 2001

(2)-Cisapride 4-hydroxylation 13.3 0.15 0.011 rCYP2C8 Desta et al., 2001(+)-Cisapride 4-hydroxylation 12.6 0.24 0.019 rCYP2C8 Desta et al., 2001Cyclosporine Total oxidative metabolism 0.40 rCYP2C8 Karlsson et al., 2013Dapsone N-hydroxylation 58-75 0.440 0.0059-0.0076 rCYP2C8 Winter et al., 2000Dibenzylfluorescein O-debenzylation 1.0 0.4d 0.4d n/a Miller et al., 2000

29.16 0.79 0.027 rCYP2C8 Ghosal et al., 20031.9 (1.3) (0.68) THLE Donato et al., 2004

Diclofenac 49-hydroxylation 630 1.2b,d 0.0019b,d rCYP2C8 Mancy et al., 19995-hydroxylation 280 7b,d 0.025b,d rCYP2C8 Mancy et al., 1999

DY-9760e Imidazole oxidation (M8) 2.6 0.0732 0.028 rCYP2C8 Tachibana et al., 2005N-dealkylation (DY-9836) 15.2 0.0231 0.0015 rCYP2C8 Tachibana et al., 2005O-demethylation (M5) 3.1 0.0128 0.0041 rCYP2C8 Tachibana et al., 2005Phenyl hydroxylation (M3) 2.5 0.2955 0.12 rCYP2C8 Tachibana et al., 2005

(continued )

180 Backman et al.

TABLE 4—Continued


Eicosapentaenoic acid Total oxidative metabolism 5.4 6.2d 1.1d rCYP2C8 Barbosa-Sicard et al., 2005Estradiol-17b-glucuronide 2-hydroxylation 88 1.86 0.021 rCYP2C8 Delaforge et al., 2005Ethanol Acetaldehyde formation 8,300 (0.0043) (,0.001) rCYP2C8 Hamitouche et al., 2006Eupatilin 4-O-demethylation 4.5 0.94 0.21 rCYP2C8 Lee et al., 2007Felodipine Total oxidative metabolism 1.1 rCYP2C8 Karlsson et al., 2013Fenretidine 49-hydroxylation 2.2 282f 130f rCYP2C8 Illingworth et al., 2011

49-oxidation 5.0 30f 6.0f rCYP2C8 Illingworth et al., 2011R-Fluoxetine N-demethylation 153.8 (6.08) (0.040) rcCYP2C8 Wang et al., 2014bS-Fluoxetine N-demethylation 195.0 (6.68) (0.034) rcCYP2C8 Wang et al., 2014bFluvastatin (acid, parent) 5-hydroxylation 2.8 0.13 0.046 rCYP2C8 Fischer et al., 1999Gliclazide 6b-hydroxylation 984 0.63 ,0.001 rCYP2C8 Elliot et al., 2007

7b-hydroxylation 346 0.06 ,0.001 rCYP2C8 Elliot et al., 2007Glyburide (glibenclamide) Total oxidative metabolism 10.2 0.9 0.09 rCYP2C8 Zharikova et al., 2009

7.7 2.5 0.32 rCYP2C8 Zhou et al., 20100.08 rCYP2C8 Varma et al., 2014

Halofantrine N-debutylation 156 0.039 ,0.001 rCYP2C8 Baune et al., 1999Ibrolipim (NO-1886) O-deethylation (M2) 28.4–53.9 0.0334–0.10 0.0012–0.0019 rCYP2C8 Morioka et al., 2002R-Ibuprofen 2-hydroxylation 3.5–74 rCYP2C8 Hamman et al., 1997

282 9.4 0.033 rCYP2C8 Chang et al., 2008341.3 4.92e 0.014e rCYP2C8 Yu et al., 2013b

S-Ibuprofen 2-hydroxylation 292 5.4 0.018 rCYP2C8 Chang et al., 2008388.8 3.02e 0.0078e rCYP2C8 Yu et al., 2013b

Imatinib N-demethylation 1.4 0.408 0.29 rCYP2C8 Nebot et al., 20104.28 4.07 0.95 rCYP2C8 Filppula et al., 2013a5 0.553 0.1 rCYP2C8 Khan et al., 2015

Isotretinoin (13-cis-retinoicacid)

4-hydroxylation 13.8 134.6g 9.8g rCYP2C8 Rowbotham et al., 2010

L-775,606 Hydroxylation (M1) 42 0.62 0.015 rCYP2C8 Prueksaritanont et al., 2000N-dealkylation (M2) 64 0.03 ,0.001 rCYP2C8 Prueksaritanont et al., 2000

Loperamide N-demethylation 11.3 0.0052 ,0.001 rCYP2C8 Kim et al., 2004Magnolin O-demethylation (M1) 17.7 1.9 0.11 rCYP2C8 Kim et al., 2011a

O-demethylation (M2) 21.2 0.3021 0.014 rCYP2C8 Kim et al., 2011aHydroxylation (M4) 29.7 0.7099 0.024 rCYP2C8 Kim et al., 2011a

Mavoglurant Total oxidative metabolism 17.1 5.06 0.30 rCYP2C8 Walles et al., 2013Mirodenafil N-dealkylation (SK3541) 121 0.85 0.0070 rCYP2C8 Lee et al., 2008Montelukast 36-hydroxylation (M6) 0.050 0.18 3.6 rCYP2C8 Filppula et al., 2011

0.014 ;0.24 ;17 rCYP2C8 VandenBrink et al., 20110.065 ;0.09 ;1 HLM VandenBrink et al., 20110.31 0.015 0.048 rCYP2C8 Oliveira Cardoso et al.,

201525-hydroxylation (M3) 0.33 0.002 0.006 rCYP2C8 Oliveira Cardoso et al.,

2015Morphine N-demethylation 4,800 5.41 0.0011 rCYP2C8 Projean et al., 2003bNifedipine Total oxidative metabolism 0.38 rCYP2C8 Karlsson et al., 2013Nitidine chloride Total oxidative metabolism 1.17 0.0705 0.060 rCYP2C8 Li et al., 2014bR-Norverapamil D-620 formation 56 5.3 0.095 rCYP2C8 Tracy et al., 1999

PR-22 formation 38 29 0.76 rCYP2C8 Tracy et al., 1999S-Norverapamil D-620 formation 80 14 0.18 rCYP2C8 Tracy et al., 1999

PR-22 formation 80 12 0.15 rCYP2C8 Tracy et al., 1999Olanzapine N-demethylation 30 1.370 0.046 rCYP2C8 Korprasertthaworn et al.,

2015Omeprazole 5-hydroxylation 300 3.3 0.011 rCYP2C8 Karam et al., 1996Paclitaxel 6a-hydroxylation 5.4 30 5.6 rCYP2C8 Rahman et al., 1994

4.0 (870) (220) HLM Rahman et al., 199415 0.12 0.0080 HLM Monsarrat et al., 199717 HLM Ando et al., 199826 HLM Desai et al., 199834.8 (1632) (47) HLM Fischer et al., 19984.9 1.14 0.23 rCYP2C8 Masimirembwa et al., 19996 (234) (39) rCYP2C8 Ong et al., 2000

12.2 (142) (12) HLM Ong et al., 20002.85 5.667 2.0 rCYP2C8 Ohyama et al., 2000

2.58–4.55 0.224–0.583 0.070–0.19 HLM Ohyama et al., 20006.8 3.0d 0.44d rCYP2C8 Yamazaki et al., 2000

15 0.8 0.053 rCYP2C8 Dai et al., 20014.3 (147) (34) rCYP2C8 Fujino et al., 2001

27.4 (359) (13) HLM Fujino et al., 200116.2 29.8 1.8 rCYP2C8 Soyama et al., 200115 1.950 0.13 HLM Cresteil et al., 20029.3 (60.9) (6.8) HLM Václavíková et al., 2003

13.3 (109.1) (8.2) HLM Donato et al., 200416.3 (81.0) (5.0) THLE Donato et al., 20047.50 (70.2) (9.4) HLM Polasek et al., 20048.3 1.718 0.21 rCYP2C8 Zhang et al., 2009b

18.3 (250) (14) HLM Zhang et al., 2009b

(continued )


TABLE 4—Continued


4.17 2.4 0.58 rCYP2C8 Gao et al., 20102.33 4.05 1.7 rCYP2C8 Hanioka et al., 20103.7 0.29b 0.078b rcCYP2C8 Kaspera et al., 20112.58 3.53 1.4 rCYP2C8 Wattanachai et al., 20117.08 (137) (19) HLM Wattanachai et al., 20118.65 69.83 8.1 rCYP2C8 Yu et al., 2013b5.2 (222.1) (43) HLM Wang et al., 2014a

5.41–15.9 (52.6–230) (3.3–26) HLM Kudo et al., 2015Pafuramidine maleate

(DB289)O-demethylation (M1) 2.6 0.12 0.046 rCYP2C8 Wang et al., 2006

Perospirone Total oxidative metabolism 1.09 1.93 1.8 rCYP2C8 Kitamura et al., 2005Perphenazine N-dealkylation 28 1.35 0.048 rCYP2C8 Olesen and Linnet, 2000Phenazone (antipyrine) N-demethylation 30,400 (156.4) (0.0051) rCYP2C8 Engel el al., 1996

3-hydroxylation 22,000 (43.9) (0.0020) rCYP2C8 Engel el al., 19964-hydroxylation 61,000 (140.9) (0.0023) rCYP2C8 Engel el al., 1996

Phenprocoumon S-49-hydroxylation 3.78 0.027 0.0071 rCYP2C8 Ufer et al., 2004Pioglitazone M-IV formation 10.2 9.2 0.91 rCYP2C8 Tornio et al., 2008b

9.8 (640) (65) HLM Tornio et al., 2008b29.5 1.702 0.058 rCYP2C8 Muschler et al., 2009

R483 Hydroxylation (M1) 1.4 (1,000) (700) n/a Bogman et al., 2010Repaglinide Total oxidative metabolism 2.8 4.9 1.8 rCYP2C8 Kajosaari et al., 2005a

M1 formation 25 0.08 0.003 rCYP2C8 Säll et al., 2012M4 formation 5.7 0.35 0.061 rCYP2C8 Säll et al., 2012M4 formation 9.0 (130) (14) HLM Säll et al., 2012M4 formation 28 13c 0.46c Hep Säll et al., 2012M4 formation 13 (18) (1.4) S9 Säll et al., 2012

12.01 15.69e 1.3e rCYP2C8 Yu et al., 2013bRosiglitazone p-hydroxylation 44 (2,900) (66) rCYP2C8 Baldwin et al., 1999

4.3–7.7 (550–883) (93–130) HLM Baldwin et al., 1999N-demethylation 10 (2,430) (240) rCYP2C8 Baldwin et al., 1999p-hydroxylation 4.0 0.42b 0.11b rcCYP2C8 Kaspera et al., 2011N-demethylation 2.9 0.38b 0.13b rcCYP2C8 Kaspera et al., 2011

Selegiline Demethylation 82 3 0.04 rCYP2C8 Hidestrand et al., 2001Levomethamphetamine

formation630 7 0.01 rCYP2C8 Hidestrand et al., 2001

Seratrodast 49-hydroxylation 28.2 0.1438 0.0051 rCYP2C8 Kumar et al., 19975-methylhydroxylation 32.9 0.4983 0.015 rCYP2C8 Kumar et al., 1997

Sildenafil Total oxidative metabolism 0.055 rCYP2C8 Karlsson et al., 2013Simvastatin acid M1 formation 88 2,800 32 rCYP2C8 Prueksaritanont et al., 2003

M2 formation 36 850 24 rCYP2C8 Prueksaritanont et al., 2003M3 formation 16 600 38 rCYP2C8 Prueksaritanont et al., 2003

T-5 N-oxidation 1.6 0.22 0.14 rCYP2C8 Li et al., 2014aTacrolimus Total oxidative metabolism 0.19 rCYP2C8 Karlsson et al., 2013Tanshinol borneol ester M3 formation 45.2 4.28h 0.095h rCYP2C8 Liu et al., 2010bTerbinafine Deamination 24.8 0.512 0.021 rCYP2C8 Vickers et al., 1999

N-demethylation 13.6 2.06 0.15 rCYP2C8 Vickers et al., 1999Side chain oxidation 26.4 0.825 0.031 rCYP2C8 Vickers et al., 1999Total oxidative metabolism 15.3 4.47 0.29 rCYP2C8 Vickers et al., 1999

R-Tofisopam M3 formation 52 0.43 0.0083 rCYP2C8 Cameron et al., 2007Tolbutamide Hydroxylation 650.5 rCYP2C8 Veronese et al., 1993

531 0.39 ,0.001 rCYP2C8 Rettie et al., 19941,160 (10.2) (0.0088) rCYP2C8 Pang et al., 2012

Torsemide (torasemide) Methyl hydroxylation 184 1.8 0.0098 rCYP2C8 Miners et al., 2000170 (35) (0.21) rCYP2C8 Ong et al., 2000

Tozasertib (MK 0457, VX6,VX 680)

N-demethylation 64 129 2.0 rCYP2C8 Ballard et al., 2007

Tretinoin (all-trans-retinoicacid)

4-hydroxylation 6.1 0.18 0.030 rCYP2C8 Nadin and Murray, 1999

4-hydroxylation 50 1.211 0.024 rCYP2C8 Marill et al., 200018-hydroxylation 17 0.033 0.0019 rCYP2C8 Marill et al., 20005,6-epoxy metabolite

formation130 0.450 0.0035 rCYP2C8 Marill et al., 2000

4-hydroxylation 13.4 4.8 0.36 rCYP2C8 Thatcher et al., 2010Troglitazone Quinone formation 2.7 4.2d 1.6d rCYP2C8 Yamazaki et al., 1999bVerapamil O-demethylation 48.4 (13) (0.27) rCYP2C8 Busse et al., 1995

Total oxidative metabolism 0.39 rCYP2C8 Karlsson et al., 2013R-Verapamil D-617 formation 127 8.0 0.063 rCYP2C8 Tracy et al., 1999

Norverapamil formation 127 6.9 0.054 rCYP2C8 Tracy et al., 1999PR-22 formation 33 2.2 0.067 rCYP2C8 Tracy et al., 1999

S-Verapamil D-617 formation 185 8.0 0.043 rCYP2C8 Tracy et al., 1999Norverapamil formation 154 15 0.097 rCYP2C8 Tracy et al., 1999PR-22 formation 141 1.6 0.011 rCYP2C8 Tracy et al., 1999

(continued )

182 Backman et al.

In addition, CYP2C8 participates to various degree tothe metabolism of several other anticancer agents, aslisted in Table 1.2. Antidiabetic Agents. The nonsulfonylurea insulin

secretagogue repaglinide is metabolized primarily byCYP2C8 (Table 4) and CYP3A4, but it also undergoesdirect glucuronidation by uridine-59-diphosphoglucuro-nosyltransferase (UGT) 1A1 (Bidstrup et al., 2003;Kajosaari et al., 2005a,b; Gan et al., 2010). In addition,there is in vitro data suggesting that aldehyde de-hydrogenase is involved in its metabolism (Säll et al.,2012). Moreover, repaglinide is a substrate of thehepatic uptake transporter organic anion-transportingpolypeptide (OATP) 1B1 (Niemi et al., 2005b, 2011). Theformation of the main metabolites of repaglinide, anoxidized dicarboxylic acid (M2) and, in particular, 39-hydroxyl repaglinide (M4), is largely dependent onCYP2C8, whereas the less important aromatic aminemetabolite (M1) is primarily formed by CYP3A4 (Bidstrupet al., 2003; Kajosaari et al., 2005a,b).Pioglitazone, a thiazolidinedione peroxisome prolif-

erator activated receptor (PPAR) g agonist, is primarilymetabolized by CYP2C8 in vitro, with smaller contri-butions by CYP3A4 and the extrahepatic CYP1A1(Jaakkola et al., 2006c; FDA, 2013a). In vitro, CYP2C8forms the pharmacologically active hydroxypioglita-zone (M-IV) and ketopioglitazone (M-III) (Jaakkolaet al., 2006c; Tornio et al., 2008b), which are the mainmetabolites in human serum with concentrations equalto or greater than those of the parent drug (Ecklandand Danhof, 2000). In vivo studies support the centralrole of CYP2C8 in pioglitazone metabolism observedin vitro (section VI.C.2).Rosiglitazone, another PPAR-g agonist, is also a

substrate of CYP2C8. In vitro, it undergoes CYP2C8-mediated p-hydroxylation andN-demethylation (Table 4),followed by sulfate and glucuronic acid conjugation(Baldwin et al., 1999; Kaspera et al., 2011; FDA,2014a). CYP2C9 also participates in its metabolismto a minor extent (Baldwin et al., 1999). Rosiglitazonep-hydroxylation is recommended by the Food and

Drug Administration (FDA) as a marker reaction forin vitro CYP2C8 activity (http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm). In vitro,troglitazone is metabolized by CYP2C8 to its qui-none metabolite (M3) (Table 4) at a two- to eightfoldhigher rate than by CYP2C19, CYP3A4, and CYP2C9(Yamazaki et al., 1999b). M3 is a minor metabolite oftroglitazone, but it has been suggested to be responsiblefor the drug-induced hepatotoxicity associated withtroglitazone use (Yamazaki et al., 1999b; Smith,2003). Furthermore, the thiazolidinedione R483 isprimarily metabolized by CYP2C8 and CYP2C19 invitro (Bogman et al., 2010). CYP2C8 catalyzes theformation of the weakly active M1 metabolite (Table 4)and its further metabolism to M4, which is the mainmetabolite of R483 in plasma. In turn, CYP2C19 formsM2, which shows similar pharmacological activity asparent R483 (Bogman et al., 2010).

Additionally, CYP2C8 is involved, to a minor extent,in the metabolism of the sulfonylureas gliclazide,glyburide, and tolbutamide, the dipeptidyl peptidase 4inhibitor sitagliptin, and the PPARa agonist sipoglita-zar (Table 1; Relling et al., 1990; Srivastava et al., 1991;Veronese et al., 1993; Elliot et al., 2007; Vincent et al.,2007; Zharikova et al., 2009; Nishihara et al., 2012).Tolbutamide p-methyl hydroxylation has been used asa marker reaction for CYP2C8 activity in several invitro studies. However, its Michaelis-Menten constant(Km) for CYP2C8 is very high (.530 mM; Table 4), andit is effectively metabolized by CYP2C9 at lowerconcentrations.

3. Antimalarial Agents. The 4-aminoquinoline de-rivative amodiaquine, widely used for treatment ofmalaria for more than 60 years, is a substrate ofCYP2C8 (Li et al., 2002). It is also metabolized by theextrahepatic enzymes CYP1A1 and CYP1B1 to a minorextent (Li et al., 2002). Amodiaquine N-deethylation is afrequently used in vitro marker reaction for CYP2C8because of its high affinity (Km typically around 2 mM)and high turnover rate (Table 4).N-desethylamodiaquine,

TABLE 4—Continued


Vidupiprant (AMG 853) t-butyl hydroxylation (M2) 1.21 0.031 0.026 rCYP2C8 Foti et al., 2012Cyclopropyl hydroxylation

(M3)49.1 0.250 0.0051 rCYP2C8 Foti et al., 2012

Vitamin A (retinol) 4-hydroxylation 71 1.73 0.024 rcCYP2C8 Leo et al., 1989Zopiclone N-demethylation 71 2.5 0.035 rCYP2C8 Becquemont et al., 1999

N-oxidation 59 1.0 0.017 rCYP2C8 Becquemont et al., 1999

5-MeO-DIPT, 5-methoxy-N,N-diisopropyltryptamine; BYZX, [(E)-2-(4-((diethylamino)methyl)benzylidene)-5,6-dimethoxy-2,3-dihydroinden-one]; CLint, intrinsic clearance;Hep, hepatocytes; HIM, human intestinal microsomes; HLM, human liver microsomes; Km, Michaelis-Menten constant; n/a, not available; rCYP2C8, recombinant CYP2C8;rcCYP2C8, reconstituted CYP2C8; S9, S9 fraction; THLE, immortalized human liver epithelial cells; Vmax, maximal velocity.

aCalculated as Vmax/Km.bkcat reported instead of Vmax, CLint calculated as kcat/Km.cVmax as pmol/min/106 cells, CLint as pmol/min/106 cells/mM.dVmax as 1/min, CLint as 1/min/mM.eVmax as arbitrary unit (AU), CLint as AU/mM.fVmax as unit/min, CLint as unit/min/mM.gVmax as counts/s/s, CLint as counts/s/s/mM.hVmax as AUC×min/nmol, CLint as AUC×min/nmol/mM.





which is the main metabolite of amodiaquine, is assumedto be the main entity responsible for the pharmacologicalresponse to amodiaquine (Churchill et al., 1985; Mountet al., 1986).Chloroquine, also a 4-aminoquinoline, is mainly

metabolized to its N-desethyl metabolite by CYP2C8(Table 4) and CYP3A4, with a small contribution byCYP2D6 in vitro (Kim et al., 2003; Projean et al., 2003a).Furthermore, CYP2C8 also seems to play a small rolein the in vitro metabolism of the antimalarial agentsdapsone, halofantrine, and piperaquine (Table 1; Bauneet al., 1999; Winter et al., 2000; Lee et al., 2012c).4. Lipid-lowering Drugs. CYP2C8 participates to a

small extent in the metabolism of several HMG-CoAreductase inhibitors (statins), but it has a major role forthe biotransformation of cerivastatin. Cerivastatin isextensively metabolized in humans (Boberg et al., 1997;Mück, 2000). Parent cerivastatin (acid) is metabolizedby CYP2C8 and CYP3A4, whereas cerivastatin lac-tone is predominantly metabolized by CYP3A4 (Boberget al., 1997; Wang et al., 2002; Fujino et al., 2004). Theformation of the major metabolite of cerivastatin,6-hydroxycerivastatin (M-23), is primarily mediated byCYP2C8, whereas both CYP2C8 and CYP3A4 producedemethylcerivastatin (M1) (Wang et al., 2002; Kasperaet al., 2010). The notorious in vivo interaction between

gemfibrozil and cerivastatin is discussed in sectionVI.C.4.

The parent simvastatin lactone is either oxidized byCYP3A4/5 or hydrolyzed to its acid form, which ispharmacologically active (Prueksaritanont et al., 1997,2003). In human liver microsomes (HLM), the metabo-lism of simvastatin acid was catalyzed primarily($80%) by CYP3A4/5, with a smaller contribution(#20%) by CYP2C8 (Prueksaritanont et al., 2003).Recombinant CYP2C8 formed all three simvastatinacid metabolites (M1-M3) observed in HLM (Table 4;Prueksaritanont et al., 2003). In vitro, fluvastatin ismainly metabolized by CYP2C9 into three metabolites,but CYP1A1, CYP2C8, CYP2D6, and CYP3A4 form5-hydroxyfluvastatin (Fischer et al., 1999). Both atorvas-tatin (acid) and its lactone are primarily metabolizedby CYP3A4 to their hydroxylated metabolites in vitro,but CYP2C8 is involved in the formation of p-hydroxyatorvastatin acid to a small extent (Jacobsen et al.,2000b). Furthermore, pitavastatin acid is metabolizedby CYP2C9 and CYP2C8 in vitro, whereas its lactone ismetabolized by CYP3A4 and CYP2D6 (Fujino et al.,2004).

5. Other Drugs. Early in vitro studies concludedthat the leukotriene receptor antagonist montelukastis mainly metabolized by CYP2C9 and CYP3A4 (Chiba

Fig. 3. Molecular descriptors of drugs classified as "major" or "intermediate" CYP2C8 substrates in Table 1. The molecular descriptors were obtainedfrom SciFinder (American Chemical Society).

184 Backman et al.

et al., 1997), whereas the role of CYP2C8 was notevaluated. However, in vitro studies performed morethan a decade later demonstrated that CYP2C8 is thekey enzyme involved in the oxidative metabolism ofmontelukast (Filppula et al., 2011; VandenBrink et al.,2011). CYP2C8 catalyzes the main metabolic pathwayof montelukast; formation of the pharmacologicallyactive 36-hydroxymontelukast (M6), and its subsequentmetabolism to the secondary metabolite M4, a dicar-boxylic acid (Table 4). In addition, CYP2C8 forms 25-hydroxymontelukast (M3) (Filppula et al., 2011). Thesein vitro findings are in agreement with X-ray crystal-lography data, demonstrating a ligand-protein bindinginteraction between montelukast and CYP2C8 (Schochet al., 2008). The montelukast molecule was positionedwith its benzyl ring in close proximity to the heme ironof CYP2C8. The montelukast metabolites M3, M4, andM6 formed by CYP2C8 in vitro, all result from theoxidation of the benzyl ring of montelukast.The novel prolyl hydroxylase inhibitor daprodustat

(GSK1278863), an antianemic agent, is primarily me-tabolized by CYP2C8, with a smaller contribution byCYP3A4 in vitro (Johnson et al., 2014). It seems tobe more sensitive than repaglinide to CYP2C8 inhibi-tion by gemfibrozil in vivo (section VI.C.8; Johnsonet al., 2014).The novel nonstructural 5B nonnucleoside polymer-

ase inhibitor dasabuvir is extensively metabolized byCYP2C8, with a small contribution by CYP3A (FDA,2014g). CYP2C8 also plays an intermediate/small rolein the metabolism of the nonstructural protein 3/4 Aprotease inhibitor paritaprevir and nonstructural pro-tein 5A inhibitor ombitasvir (FDA, 2014g; Menon et al.,2015). However, no in vitro metabolism data have yetbeen published for these compounds.The prostacyclin analog treprostinil is primarily me-

tabolized byCYP2C8, followed byCYP2C9 in vitro (FDA,

2009b). Incubation of treprostinil with recombinantCYP2C8 for 15 minutes resulted in a 95% depletion oftreprostinil concentrations, whereas only 22% was con-sumed by recombinant CYP2C9. CYP2C8 seems to be ofimportance in the in vivo pharmacokinetics of treprosti-nil (FDA, 2009b).

The sedative agent zopiclone is metabolized byCYP2C8 and CYP3A4 in vitro (Becquemont et al.,1999). In HLM, CYP2C8 was the main enzyme catalyz-ing N-demethylation of zopiclone, followed by CYP2C9and CYP3A4. CYP2C8 also participated in the forma-tion ofN-oxide zopiclone, together with CYP3A4 (major)and CYP2C9 (Becquemont et al., 1999). However, inanother in vitro study, montelukast (CYP2C8 inhibitor)and gemfibrozil (CYP2C8 and CYP2C9 inhibitor) hadno effect on the elimination of clinically relevant con-centrations of zopiclone (Tornio et al., 2006), supportingin vivo data showing a lack of effect of gemfibrozil onzopiclone concentrations in healthy subjects (sectionVI.C.8).

Based on in vitro studies, CYP2C8 likely playsan intermediate role in the elimination of 9cUAB30,alitretionin, amiodarone, cisapride, fenretinide, fluox-etine, irosustat, isotretionin, loperamide, olanzapine,olodaterol, propanoic acid, dronedarone, tazarotenicacid, verapamil, and vidupiprant (AMG 853) (Table 1).For instance, CYP2C8 catalyzes dealkylation of bothenantiomers of the calcium channel blocker verapamiland its metabolite norverapamil (Busse et al., 1995;Tracy et al., 1999). Tazarotenic acid, the activemoiety ofthe antipsoriatic agent tazarotene, is mainly metabo-lized by CYP2C8 and flavin-containing monooxyge-nases in vitro (Attar et al., 2003). When tazarotenicacid was incubated with 10 individual recombinantCYP enzymes, only CYP2C8 markedly catalyzed sul-foxidation, which is the main metabolic pathway oftazarotenic acid.

Fig. 4. The number of "major" and "intermediate" CYP2C8 substrates by drug class, as listed in Table 1.


There is a vast amount of in vitro data suggesting thatCYP2C8 may be of relevance in the metabolism of anumber of other drugs (Table 1). For themajority of thesecompounds, the role of CYP2C8 in their in vivo elimina-tion is likely to be small or negligible. However, forsome drugs, the in vivo contribution of CYP2C8 to theirmetabolism cannot be estimated based on availableinformation, andmay, in fact, exceed 20%. Alternatively,CYP2C8may become a determinant in their metabolismafter inhibition of other enzymes important for theirelimination. For instance, CYP2C8 is involved in themetabolism of seratrodast, a thromboxane A2 receptorantagonist in vitro (Kumar et al., 1997). The mainmetabolic pathway of seratrodast, 5-methylhydroxylation,is primarily catalyzedbyCYP3AandCYP2C9, butCYP2C8contributes to a small degree. However, CYP2C8 is amajor contributor to seratrodast 49-hydroxylation, aminormetabolic route (Kumar et al., 1997).6. Glucuronide Metabolites. Several glucuronide me-

tabolites have been reported to undergo metabolism byCYP2C8, including clopidogrel acyl 1-b-D-glucuronide,desloratadine glucuronide, diclofenac acyl glucuronide,

estradiol-17b-glucuronide, gemfibrozil 1-O-b glucuronide,licofelone 1-O-acyl glucuronide, Lu AA34893 carbamoylglucuronide, 2-[[5,7-dipropyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy]-2-methylpropanoic acid (MRL-C)acyl glucuronide, and sipoglitazar b-1-O-acyl glucuronide(see Table 2 for references). Thus, CYP2C8 makes yetanother exception to the old concept that drugmetabolismis divided into sequential phase I and phase II reactions,i.e., functionalizationand conjugation, respectively (Fig. 5).

Kumar et al. (2002) demonstrated the first example ofCYP2C8-mediated metabolism of a glucuronide conju-gate when they showed that the conversion of diclofenacacyl glucuronide to its 49-hydroxy derivative is exclusivelymediated by CYP2C8 in vitro. In 2005, it was reportedthat CYP2C8 is also able to directly catalyze the2-hydroxylation of estradiol-17b-glucuronide in vitro(Delaforge et al., 2005). Docking of the glucuronide ofestradiol into the crystal structure of CYP2C8 showedthat the active site is large enough to inhabit theconjugate. Also the fetal CYP3A isoformCYP3A7 oxidizedestradiol-17b-glucuronide, but CYP2C8 was five timesmore active than CYP3A7. However, CYP3A4 was not

Fig. 5. Schematic illustration of the interaction between CYP2C8 and its glucuronide substrates. CYP2C8 and the UGT are localized on opposite sitesof the endoplasmic membrane (A). The drug is glucuronidated by the UGT (B). Hereafter, the glucuronide crosses the endoplasmic membrane andbinds into CYP2C8 (C). Then, the glucuronide is either metabolized by CYP2C8 and released as a metabolite (D, left), e.g., desloratadine glucuronide,and diclofenac acyl glucuronide, or it is metabolized to a reactive agent that inactivates CYP2C8 (D, right), as for clopidogrel acyl 1-b-D-glucuronide andgemfibrozil 1-O-b glucuronide. CYP2C8 has been suggested to exist as a dimer (Hu et al., (2010), Schoch et al., (2004)). ER, endoplasmic reticulum.

186 Backman et al.

able to metabolize estradiol-17b-glucuronide (Delaforgeet al., 2005). Moreover, the acyl glucuronide of the dualPPAR a/b agonistMRL-Cwas oxidized byCYP2C8 and toaminor extent byCYP3A4, but not byCYP2C9 (Kochanskyet al., 2005). Furthermore, the main elimination pathwayof licofelone, a dual inhibitor of cyclooxygenases 1 and 2and 5-lipoxygenase, is glucuronidation of its carboxylicacid metabolite, followed by CYP2C8-catalyzed hydroxyl-ation of the acyl glucuronide M1 to form the hydroxylatedglucuronide M3 (Albrecht et al., 2008).For two compounds, the formation of an unconjugated

hydroxyl metabolite involves oxidation and subsequentdeconjugation of a glucuronide metabolite. In vitro, theantidiabetic agent sipoglitazar was first glucuronidatedto sipoglitazar b-1-O-acyl glucuronide (sipoglitazar-G1).Sipoglitazar-G1 was then metabolized to the main metab-olite M-I by O-dealkylation by CYP2C8 and subsequentdeconjugation (Nishiharaet al., 2012).A similar findingwasrecently observed for desloratadine (Kazmi et al., 2015). Themain metabolite of desloratadine, 3-hydroxydesloratadine,which is active, was formed via CYP2C8-mediated oxida-tion of desloratadine glucuronide anda deconjugation event(Kazmi et al., 2015). Thus, it seems that phase II metabo-lism occurs before phase I for these compounds (Fig. 5).Also the glucuronide metabolites of clopidogrel, gem-

fibrozil, and Lu AA34893 are likely to be substrates ofCYP2C8 (Ogilvie et al., 2006; Baer et al., 2009; Kazmiet al., 2010; Tornio et al., 2014). All three compounds aremetabolism-dependent inhibitors of CYP2C8, as dis-cussed in sections V.B and VI.B.

B. Endogenous and Natural Compounds

CYP2C8 metabolizes some endogenous and natu-ral compounds (Table 3). CYP2C8 participates inthe metabolism of arachidonic acid to biologicallyactive epoxyeicosatrienoic acids (e.g., 11-, 13-, or 15-hydroxyeicosatrienoic acid), involved in the regulation ofnumerous physiologic processes, e.g., vascular function,blood pressure regulation, pancreatic peptide hormonesecretion, and platelet aggregation (Daikh et al., 1994;Rifkind et al., 1995; Zeldin et al., 1995). The roles ofCYP2C8 and other CYP enzymes in inflammation,cardiovascular disease, and cancer were recentlyreviewed by Chen andWang (2015) and Fleming (2014).CYP2C8 and CYP3A enzymes have generally been

considered to be the primary CYPs involved in themetabolism of all-trans-retinoic acid, the active form ofvitamin A (retinol) (Leo et al., 1989; Nadin and Murray,1999; Marill et al., 2000). All-trans-retinoic acid isinvolved in gene transcription, cell division, and differ-entiation (Tzimas and Nau, 2001; Marill et al., 2003;Duester, 2008). According tomore recent data, however,CYP26A1 and CYP3A4 are the primary determinants ofall-trans-retinoic acid metabolism in humans, whereasthe role of CYP2C8 is of smaller importance (Thatcheret al., 2010). In vitro, CYP2C8 also catalyzes themetabolism of other retinoids, including 9-cis-retinoic

acid, 13-cis-retinoic acid, and 9cUAB30 (Marill et al.,2002; Gorman et al., 2007).

Some in vitro data suggest that CYP2C8 may contrib-ute to the metabolism of the steroids 17b-estradiol,progesterone, and testosterone (Waxman et al., 1991;Spink et al., 1992, 1994). However, there seems to be noevidence for a role of CYP2C8 in the metabolism ofandrogens in vivo. Although CYP2C8 participates in themetabolism of several endogenous compounds, no car-diovascular or other potentially CYP2C8-related adverseeffects were observed in the Helsinki Heart Study, inwhich over 2000 middle-aged men with primary dyslipi-demia ingested the strong CYP2C8 inhibitor gemfibrozil600 mg twice daily for several years (Frick et al., 1987).

Furthermore, some natural compounds have beenreported to undergo metabolism by CYP2C8 in vitro(Table 3). CYP2C8 and CYP3A4 are the primaryenzymes involved in the in vitro metabolism of1-hydroxyl-2,3,5-trimethoxyxanthone, a constituent ofthe Tibetan medicinal plant Halenia elliptica (Fenget al., 2014). CYP2C8 is responsible for the mainmetabolic pathway of silybin, the active component ofsilymarin in vitro (Jancova et al., 2007). The CYP2C8inhibitor quercetin inhibited silybin O-demethylationby 80% in HLM, and recombinant CYP2C8 was themajor enzyme formingO-demethyl silybin, with a smallcontribution by CYP3A4. Furthermore, CYP2C8 is themajor enzyme responsible for the in vitro metabolism oftanshinol borneol ester, a combination of the naturalcompounds danshensu and borneol (Liu et al., 2010a).Recombinant CYP2C8 generated all five tanshinolborneol metabolites (M1-M5) observed in HLM incuba-tions, whereas recombinant CYP3A4 only produced theM4 metabolite.

IV. Pharmacogenetics

Nearly 100 nonsynonymous single nucleotide varia-tions (SNV) and short deletions, as well as essentialsplice site variants have been found in the CYP2C8gene. The variants described in the literature, dbSNPdatabase, or the 1000 Genomes project database arelisted in Table 5, together with their continentalfrequencies and predicted or experimentally deter-mined effects on protein function. The vast majority ofthe nonsynonymous variants are rare and occur atminor allele frequencies of 0.01 or less in all investi-gated populations.

A. Population Genetics

Three alleles, known as CYP2C8*2, *3, and *4,account for the majority of nonsynonymous variabilityof CYP2C8 in humans. Their frequencies differ signif-icantly both between and within continental popula-tions (Table 5, Fig. 6).

The CYP2C8*2 allele (c.805A.T, p.Cys266Phe) oc-curs mostly in individuals with a sub-Saharan African


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sortium,2

012).S

IFTan

dPolyP

hen

pred

iction

sof

thepo

ssible

impa

ctof

aminoacid

subs

titution

son

proteinfunctionwereob

tained

usingtheVariantEffectPredictor

(Kumar

etal.,20

09;Adz

hube

iet

al.,20

10;McL

aren

etal.,20

10).*-allele

nom

enclature

was

retrieve

dfrom

theHuman

Cytochr

omeP45

0(C

YP)AlleleNom

enclatur

eDatab

ase(w

ww.cyp

alleles.ki.se).

*-allele

dbSNPID

Location

Nucleo

tide

Chan

geAminoAcidChan

ge

Enzy

meActivity

VariantAlleleFrequ

ency

InSilicoPrediction

African

Europe

anSou

thAsian

Eas

tAsian

American

SIF

TPolyP

hen

InVivo

InVitro

rs14

2470

035

Exo

n1

c.1A

.G

p.Met1?

0.00

450

00

0de

leteriou

spr

obab

lyda

mag

ing

rs37

3001

219

Exo

n1

c.7C

.A

p.Pro3T

hr

——

——

—tolerated

benign

rs53

0027

098

Exo

n1

c.40

A.T

p.Met14

Leu

00

0.00

10

0tolerated

benign

rs20

2131

138

Exo

n1

c.63

A.T

p.Arg21

Ser

——

——

—de

leteriou

sbe

nign

rs26

7602

643

Exo

n1

c.77

G.A

p.Arg26

Lys

——

——

—tolerated

benign

rs37

5170

154

Exo

n1

c.14

9T.C

p.Ile5

0Thr

——

——

—tolerated

benign

rs11

3939

225

Exo

n1

c.16

7A.G

p.Asn

56Ser

——

——

—tolerated

benign

↔rs37

6132

046

Exo

n2

c.19

9G.A

p.Val67

Met

——

——

—de

leteriou

spo

ssibly

damag

ing

rs17

8517

96Exo

n2

c.24

4G.A

p.Ala82

Thr

00

00.00

10

deleteriou

sbe

nign

rs17

8517

96Exo

n2

c.24

4G.T

p.Ala82

Ser

00

00.00

10

deleteriou

sbe

nign

rs20

1449

274

Exo

n2

c.26

3T.C

p.Ile8

8Thr

00

00

0.00

14de

leteriou

sbe

nign

rs37

2299

895

Exo

n2

c.26

8A.G

p.Asn

90Asp

——

——

—tolerated

benign

rs57

8254

206

Exo

n2

c.29

3G.T

p.Gly98

Val

00

0.00

10

0de

leteriou

spr

obab

lyda

mag

ing

rs19

9931

273

Intron

2c.33

1+2T

.C

——

——

——

—

rs36

9552

457

Exo

n3

c.34

5C.A

p.Ser11

5Arg

——

——

—de

leteriou

spr

obab

lyda

mag

ing

rs20

1739

495

Exo

n3

c.36

8T.A

p.Ile1

23Asn

——

——

—de

leteriou

spo

ssibly

damag

ing

rs37

7386

087

Exo

n3

c.37

0C.T

p.Arg12

4Trp

——

——

—de

leteriou

spr

obab

lyda

mag

ing

rs36

9591

911

Exo

n3

c.37

1G.A

p.Arg12

4Gln

——

——

—de

leteriou

spr

obab

lyda

mag

ing

rs18

8111

115

Exo

n3

c.37

3C.T

p.Arg12

5Cys

0.00

080

00

0de

leteriou

spo

ssibly

damag

ing

rs13

9650

638

Exo

n3

c.38

9C.A

p.Thr

130A

sn0

00.00

10

0de

leteriou

spo

ssibly

damag

ing

rs13

9650

638

Exo

n3

c.38

9C.T

p.Thr

130Ile

00

0.00

10

0tolerated

prob

ably

damag

ing

*3rs11

5720

80Exo

n3

c.41

6G.A

p.Arg13

9Lys

0.00

830.11

830.02

970.00

10.09

94tolerated

benign

↑↓↑

rs54

0288

649

Exo

n3

c.43

0C.G

p.Arg14

4Gly

00

0.01

020

0de

leteriou

spr

obab

lyda

mag

ing

rs20

0057

634

Exo

n3

c.44

9A.G

p.His15

0Arg

——

——

—tolerated

benign

rs20

1561

213

Exo

n3

c.47

2A.G

p.Lys15

8Glu

——

——

—de

leteriou

sbe

nign

*5rs72

5581

96Exo

n3

c.47

5delA

p.Thr

159P

rofsTer19

——

——

——

—non

ers57

6554

998

Exo

n4

c.49

7C.T

p.Pro16

6Leu

——

——

—de

leteriou

spr

obab

lyda

mag

ing

*6rs14

2886

225

Exo

n4

c.51

1G.A

p.Gly17

1Ser

00

00.00

60

tolerated

benign

↔rs55

3407

481

Exo

n4

c.51

6T.A

p.Cys17

2Ter

——

——

——

—rs14

1350

682

Exo

n4

c.52

5C.A

p.Cys17

5Ter

——

——

——

—

rs11

3008

582

Exo

n4

c.52

6A.G

p.Asn

176A

sp—

——

——

deleteriou

spr

obab

lyda

mag

ing

rs20

1219

972

Exo

n4

c.53

6G.C

p.Cys17

9Ser

——

——

—tolerated

possibly

damag

ing

rs41

2868

86Exo

n4

c.54

1G.A

p.Val18

1Ile

00.01

090

00.00

29tolerated

benign

rs14

7150

224

Exo

n4

c.54

4G.A

p.Val18

2Ile

——

——

—tolerated

benign

*7rs72

5581

95Exo

n4

c.55

6C.T

p.Arg18

6Ter

——

——

——

—non

e*8

rs54

3793

530

Exo

n4

c.55

7G.A

p.Arg18

6Gln

00

0.00

10

0de

leteriou

spr

obab

lyda

mag

ing

↓rs20

1899

315

Exo

n4

c.58

1T.A

p.Phe1

94Tyr

——

——

—de

leteriou

sbe

nign

rs20

1045

618

Exo

n4

c.60

2T.A

p.Phe

201T

yr0

00

0.00

10

deleteriou

spo

ssibly

damag

ing

rs14

6962

089

Exo

n4

c.63

5G.A

p.Trp

212T

er0.00

230

00

0—

—rs14

8974

310

Exo

n5

c.64

3G.A

p.Val21

5Ile

——

——

—tolerated

benign

*13

N.A.

Exo

n5

c.66

9T.G

p.Ile2

23Met

——

——

—tolerated

benign

↔rs56

9886

323

Exo

n5

c.70

3A.G

p.Lys23

5Glu

00

00.00

10

tolerated

benign

*14

rs18

8934

928

Exo

n5

c.71

2G.C

p.Ala23

8Pro

00

00.00

10

tolerated

benign

↓rs53

7006

401

Exo

n5

c.71

3C.T

p.Ala23

8Val

——

——

—tolerated

benign

rs20

0358

471

Exo

n5

c.71

6T.C

p.Leu

239P

ro—

——

——

tolerated

benign

rs53

6085

663

Exo

n5

c.72

1C.T

p.Arg24

1Ter

0.00

080

00

0—

—

rs11

5721

02Exo

n5

c.73

0A.G

p.Ile2

44Val

0.00

680

00

0tolerated

benign

*9N.A.

Exo

n5

c.74

0A.G

p.Lys24

7Arg

——

——

—tolerated

benign

↔

(con

tinued

)

188 Backman et al.

http://www.1000genomes.org

http://www.cypalleles.ki.se

TABLE

5.—

Con

tinued

*-allele

dbSNPID

Location

Nucleo

tide

Chan

geAminoAcidChan

ge

Enzy

meActivity

VariantAlleleFrequ

ency

InSilicoPrediction

African

Europe

anSou

thAsian

Eas

tAsian

American

SIF

TPolyP

hen

InVivo

InVitro

rs14

1120

323

Exo

n5

c.76

7A.G

p.Asp

256G

ly—

——

——

deleteriou

spr

obab

lyda

mag

ing

rs52

7793

637

Exo

n5

c.78

1C.T

p.Arg26

1Trp

00

0.00

10

0de

leteriou

sbe

nign

rs37

0459

834

Exo

n5

c.78

2G.T

p.Arg26

1Leu

——

——

—de

leteriou

sbe

nign

*4rs10

5893

0Exo

n5

c.79

2C.G

p.Ile2

64Met

0.00

380.05

770.00

720

0.01

87de

leteriou

spr

obab

lyda

mag

ing

↓↑rs55

1515

028

Exo

n5

c.79

3G.A

p.Asp

265A

sn0.00

080

00

0de

leteriou

spr

obab

lyda

mag

ing

rs37

7675

927

Exo

n5

c.79

7G.T

p.Cys26

6Phe

——

——

—de

leteriou

spr

obab

lyda

mag

ing

*2rs11

5721

03Exo

n5

c.80

5A.T

p.Ile2

69Phe

0.18

910.00

40.01

230

0.01

15de

leteriou

spr

obab

lyda

mag

ing

↓↔rs37

3613

215

Exo

n5

c.81

6G.C

p.Glu27

2Asp

——

——

—tolerated

benign

*11

rs78

6375

71Exo

n6

c.82

0G.T

p.Glu27

4Ter

00

00.00

30

——

non

ers14

0599

093

Exo

n6

c.82

1A.G

p.Glu27

4Gly

——

——

—de

leteriou

sbe

nign

rs37

0806

022

Exo

n6

c.84

8A.G

p.Asn

283S

er—

——

——

tolerated

benign

rs53

7326

361

Exo

n6

c.95

5G.A

p.Val31

9Ile

00

00

0.00

14tolerated

benign

rs14

6806

199

Exo

n7

c.99

2T.C

p.Ile3

31Thr

0.00

150

0.00

410

0de

leteriou

spr

obab

lyda

mag

ing

rs14

8442

781

Exo

n7

c.10

28G.T

p.Ser34

3Ile

——

——

—tolerated

benign

rs19

9691

080

Exo

n7

c.10

60G.A

p.Glu35

4Lys

——

——

—de

leteriou

spr

obab

lyda

mag

ing

rs37

3461

548

Exo

n7

c.10

63A.T

p.Ile3

55Phe

——

——

—de

leteriou

spr

obab

lyda

mag

ing

rs45

4387

99Exo

n7

c.10

81C.T

p.Leu

361P

he0

0.00

10

00

tolerated

possibly

damag

ing

rs77

1470

96Exo

n7

c.10

93G.A

p.Gly36

5Ser

0.00

980

00

0tolerated

benign

rs14

7133

669

Exo

n7

c.10

96G.A

p.Val36

6Met

0.00

080.00

10

00.00

14de

leteriou

sbe

nign

rs37

5271

607

Exo

n7

c.11

44C.T

p.Pro38

2Ser

——

——

—de

leteriou

spr

obab

lyda

mag

ing

*10

N.A.

Exo

n7

c.11

49G.T

p.Lys38

3Asn

——

——

—de

leteriou

spr

obab

lyda

mag

ing

↔rs14

3386

810

Exo

n8

c.11

50G.A

p.Gly38

4Ser

00.00

10.00

10

0de

leteriou

spo

ssibly

damag

ing

rs55

3009

747

Exo

n8

c.11

54C.T

p.Thr

385Ile

00

0.00

10

0de

leteriou

spr

obab

lyda

mag

ing

rs26

7602

641

Exo

n8

c.11

65G.A

p.Ala38

9Thr

——

——

—tolerated

benign

rs72

5581

94Exo

n8

c.11

69T.C

p.Leu

390S

er—

——

——

tolerated

benign

rs74

4541

69Exo

n8

c.11

71C.A

p.Leu

391M

et—

——

——

deleteriou

spr

obab

lyda

mag

ing

rs20

1421

851

Exo

n8

c.11

78C.G

p.Ser39

3Cys

00

00

0.00

14de

leteriou

spr

obab

lyda

mag

ing

rs19

0807

911

Exo

n8

c.11

80G.A

p.Val39

4Met

00

00.00

10

deleteriou

spr

obab

lyda

mag

ing

rs20

1301

235

Exo

n8

c.11

87A.C

p.His39

6Pro

——

——

—de

leteriou

spo

ssibly

damag

ing

rs18

6285

658

Exo

n8

c.11

89G.A

p.Asp

397A

sn0

00

0.00

20

deleteriou

spo

ssibly

damag

ing

rs11

3669

182

Exo

n8

c.11

93A.G

p.Asp

398G

ly—

——

——

tolerated

benign

*3rs10

5096

81Exo

n8

c.11

96A.G

p.Lys39

9Arg

0.00

830.11

830.02

970.00

10.09

94tolerated

benign

↑↓↑

rs18

1982

392

Exo

n8

c.11

98G.T

p.Glu40

0Ter

00

00.00

10

——

rs66

5011

15Exo

n8

c.12

10C.G

p.Pro40

4Ala

——

——

—de

leteriou

spo

ssibly

damag

ing

↓rs15

0733

212

Exo

n8

c.12

25C.T

p.Pro40

9Ser

——

——

—de

leteriou

spr

obab

lyda

mag

ing

rs37

4605

743

Exo

n8

c.12

46A.C

p.Asn

416H

is—

——

——

deleteriou

sbe

nign

rs14

1209

951

Exo

n8

c.12

50G.T

p.Gly41

7Val

0.00

150

00

0de

leteriou

spr

obab

lyda

mag

ing

rs55

2247

471

Exo

n8

c.12

52A.T

p.Asn

418T

yr0

00.00

10

0de

leteriou

spr

obab

lyda

mag

ing

rs37

1330

493

Exo

n8

c.12

73T.C

p.Phe

425L

eu0.00

080

00

0de

leteriou

spr

obab

lyda

mag

ing

rs14

8348

784

Exo

n8

c.12

76A.G

p.Met42

6Val

——

——

—tolerated

benign

↔rs37

2999

683

Exo

n9

c.13

13A.G

p.Glu43

8Gly

——

——

—de

leteriou

spr

obab

lyda

mag

ing

rs14

3038

562

Exo

n9

c.13

24C.T

p.Arg44

2Cys

——

——

—de

leteriou

spo

ssibly

damag

ing

rs13

8495

387

Exo

n9

c.13

25G.A

p.Arg44

2His

——

——

—de

leteriou

spo

ssibly

damag

ing

rs36

9600

584

Exo

n9

c.13

27A.C

p.Met44

3Leu

——

——

—de

leteriou

sbe

nign

*12

rs38

3269

4Exo

n9

c.13

82_1

384d

elTTG

p.Val46

1del

——

——

——

—rs61

7573

18Exo

n9

c.14

13de

lAp.Val47

2Leu

fsTer23

——

——

——

—↔

rs52

9725

725

Exo

n9

c.14

14G.A

p.Val47

2Ile

00

00

0.00

29tolerated

benign

rs37

6016

142

Exo

n9

c.14

41C.T

p.Pro48

1Ser

——

——

—de

leteriou

spr

obab

lyda

mag

ing

rs14

0481

138

Exo

n9

c.14

66C.T

p.Pro48

9Leu

——

——

—de

leteriou

spr

obab

lyda

mag

ing

↔,unch

ange

dactivity;↓

,redu

cedactivity;↑,

increa

sedactivity;N

.A.,no

tav

ailable;

SIF

T,sortingintolerantfrom

tolerant


ancestry. In sub-Saharan African populations, its allelefrequency ranges from about 0.10 in a Fulani populationin Burkina Faso to 0.37 in a Mbuti pygmy population inCongo (Cavaco et al., 2005; Rower et al., 2005; Parikhet al., 2007; Kudzi et al., 2009; Speed et al., 2009;Paganotti et al., 2011, 2012; 1000 Genomes ProjectConsortium, 2012; Arnaldo et al., 2013; Marwa et al.,2014). In an African-American population in the NewYork area, the allele frequency of CYP2C8*2 was 0.10

(Martis et al., 2013). The allele is also relativelycommon in the mixed Brazilian population with afrequency of 0.06, New York area Hispanic populationwith a frequency of 0.02, and North and South Indianpopulations, with frequencies of 0.03 and 0.01, respec-tively (Suarez-Kurtz et al., 2012; Martis et al., 2013;Minhas et al., 2013; Arun Kumar et al., 2015). TheCYP2C8*2 allele is very rare or absent in East Asianand European populations, with the exception of an

Fig. 6. Global distribution of CYP2C8*2, CYP2C8*3, and CYP2C8*4 alleles. Color intensity indicates allele frequency. References are given in the text.

190 Backman et al.

allele frequency of 0.01 in a Portuguese Europeansample (Nakajima et al., 2003; Muthiah et al., 2005;Cavaco et al., 2006; Pechandova et al., 2012; Vargenset al., 2012; Martis et al., 2013; Wu et al., 2013).The CYP2C8*3 allele is a haplotype consisting of

two nonsynonymous variants (c.416G.A, p.Arg139Lysand c.1196A.G, p.Lys399Arg), which appear to be ina complete or nearly complete linkage disequilibriumin all investigated populations (1000 Genomes ProjectConsortium, 2012). The linkage disequilibrium extendsalso beyond the CYP2C8 gene, as evidenced by a strongcorrelation between the CYP2C8*3 and CYP2C9*2(rs1799853; c.430C.T, p.Arg144Cys) alleles in theSwedish population (Yasar et al., 2002). The highestallele frequencies of CYP2C8*3 are seen in individualswith a European ancestry. In European populations,the allele frequency of CYP2C8*3 ranges from 0.069 inFaroe Islanders to 0.198 in a Portuguese population,with an apparent north-to-south cline from lower tohigher frequencies (Fig. 6; Yasar et al., 2002; Hallinget al., 2005; Cavaco et al., 2006; Speed et al., 2009; 1000Genomes Project Consortium, 2012; Pechandova et al.,2012; Suarez-Kurtz et al., 2012). The allele is also quitecommon in European American and North AmericanHispanic populations, with frequencies of 0.09 and 0.08,respectively (Martis et al., 2013). In themixed Brazilianand Ecuadorian populations, its frequency is 0.08 and0.07, and in a Chilean mestizo population it is 0.06(Roco et al., 2012; Suarez-Kurtz et al., 2012; Vicenteet al., 2014). There is wide variability in the frequencyof CYP2C8*3 in sub-Saharan African populations, evenwithin a country (Cavaco et al., 2005; Rower et al., 2005;Parikh et al., 2007; Kudzi et al., 2009; Arnaldo et al.,2013; Staehli Hodel et al., 2013; Marwa et al., 2014;Paganotti et al., 2014). For example, the frequency ofCYP2C8*3was found to be 0.00 in individuals in centralTanzania and as high as 0.10 in the Mwanza region ofTanzania (Staehli Hodel et al., 2013; Marwa et al.,2014).The CYP2C8*4 (c.792C.G, p.Ile264Met) allele has

its highest frequencies in European populations, withthe allele frequency ranging from 0.04 in a Spanishpopulation to 0.07 in the Irish (Cavaco et al., 2006;Speed et al., 2009; 1000 Genomes Project Consortium,2012; Pechandova et al., 2012). Its frequency was 0.03in a European American population and a mixed Bra-zilian population (Suarez-Kurtz et al., 2012; Martiset al., 2013). In Peruvian, Colombian, Puerto Rican, andNorth American Hispanic populations, the frequencyranges from 0.01 to 0.02 (1000 Genomes Project Con-sortium, 2012;Martis et al., 2013). TheCYP2C8*4 alleleis found with a frequency of about 0.03–0.04 in Indianindividuals and 0.01 in the Pakistani (1000 GenomesProject Consortium, 2012; Minhas et al., 2013). In EastAsian populations, the frequency of CYP2C8*4 isgenerally 0.01 or less, but a frequency of 0.02 was seenin anUighur Chinese population (Nakajima et al., 2003;

Muthiah et al., 2005; Speed et al., 2009; 1000 GenomesProject Consortium, 2012; Staehli Hodel et al., 2013;Wu et al., 2013). The allele is rare in individuals witha sub-Saharan African ancestry, with a frequency ofbelow 0.01 in all investigated sub-Saharan Africanpopulations and 0.01 in anAfricanAmerican population(Cavaco et al., 2005; Rower et al., 2005; Kudzi et al.,2009; 1000 Genomes Project Consortium, 2012; Arnaldoet al., 2013; Martis et al., 2013).

In addition to the common variants, rare nonsynon-ymous CYP2C8 variants exist in all continental pop-ulations (Table 5). A number of the rare CYP2C8variants can be predicted to result in a loss-of-functionbecause of premature termination of protein syn-thesis. The c.635G.A (p.Trp212Ter) and c.721C.T(p.Arg241Ter) variants have a combined allele frequencyof 0.003 in sub-Saharan African populations, and thec.820G.T (p.Glu274Ter) and c.1198G.T (p.Glu400Ter)variants have a combined allele frequency of 0.004 inEast Asians (1000 Genomes Project Consortium, 2012).Other predicted loss-of-function CYP2C8 variants werenot found in the 1000 Genomes Project populations,and data are too scarce to estimate their populationfrequencies.

B. Functional Studies

The functional effects of CYP2C8 variants have beeninvestigated using recombinantly expressed variantproteins and HLM with different CYP2C8 genotypes.Recombinant CYP2C8.2 has been quite consistentlyassociated with an about 50% decrease in the intrinsicclearance for paclitaxel 6a-hydroxylation, comparedwith CYP2C8.1 (Dai et al., 2001; Gao et al., 2010;Yu et al., 2013b). In addition, the intrinsic clearanceof amodiaquine has been reduced by 80–90% inCYP2C8.2 and that of repaglinide by 20% comparedwith CYP2C8.1 (Parikh et al., 2007; Yu et al., 2013b).Similarly, the intrinsic clearances of arachidonic acidand tanshinol borneol ester appeared to be lower byCYP2C8.2 than by CYP2C8.1, but the differences werenot statistically significant (Dai et al., 2001; Liu et al.,2010a). On the other hand, the intrinsic clearances forcerivastatin M-23 and M-1 metabolite formation and R-and S-ibuprofen hydroxylations have been nonsignificantlyhigher in CYP2C8.2 than in CYP2C8.1 (Kaspera et al.,2010; Yu et al., 2013b). Both the SIFT or Polyphen in silicopredictionalgorithms suggest that the aminoacid change inCYP2C8.2 is deleterious for CYP2C8 activity (Table 5).

In several studies, the intrinsic clearance for pacli-taxel 6a-hydroxylation by recombinant CYP2C8.3 hasbeen between 30 and 85% lower than by CYP2C8.1 (Daiet al., 2001; Soyama et al., 2001; Gao et al., 2010; Yuet al., 2013b). Other studies employing recombinantCYP2C8.3 have shown increased intrinsic clearancefor repaglinide and cerivastatin but reduced intrinsicclearance for R- and S-ibuprofen and nearly abolishedintrinsic clearance for amodiaquine (Kaspera et al.,


2010; Parikh et al., 2007; Yu et al., 2013b). The intrinsicclearances of arachidonic acid to 11,12- and 14,15-epoxyeicosatrienoic acid and tanshinol borneol esterhave also been significantly lower by CYP2C8.3 than byCYP2C8.1 (Dai et al., 2001; Liu et al., 2010a). However,in a recent study expressing CYP2C8.3 together withcytochrome P450 reductase and cytochrome b5, theintrinsic clearance for paclitaxel 6a-hydroxylation wasabout twofold higher, that for amodiaquine about two-fold higher, that for rosiglitazone about 2.5-fold higher,and that for cerivastatin about 4.5-fold higher comparedwith CYP2C8.1 (Kaspera et al., 2011). A strongerbinding affinity of ligands to CYP2C8.3 together with anincrease in heme spin change during binding of ligandsand redox partners were suggested to partly explainthe increased catalytic activity (Kaspera et al., 2011).In one study, HLM heterozygous for the CYP2C8*3allele showed lowered paclitaxel 6a-hydroxylase activ-ity and in another study no change in amodiaquineN-deethylation compared with microsomes homozy-gous for CYP2C8*1 (Bahadur et al., 2002; Kasperaet al., 2011). Studies employing HLM heterozygous orhomozygous for CYP2C8*3 have shown increased in-trinsic clearance of pioglitazone and imatinib (Muschleret al., 2009; Khan et al., 2015). In silico predictionssuggest that neither of the amino acid changes inCYP2C8.3 affect CYP2C8 activity (Table 5). Takentogether, in vitro evidence concerning the functionaleffects of CYP2C8*3 suggests some degree of asubstrate-specific effect but is discrepant for somesubstrates in that both decreased and increased activ-ities have been reported.In three studies, paclitaxel 6a-hydroxylation intrinsic

clearance was reduced by about 70% by recombinantCYP2C8.4 compared with CYP2C8.1 (Singh et al., 2008;Gao et al., 2010; Yu et al., 2013b). Similarly, the intrinsicclearances of repaglinide and R- and S-ibuprofen havebeen 20, 50, and 53% lower by CYP2C8.4 than byCYP2C8.1, respectively (Yu et al., 2013b). On the otherhand, the intrinsic clearances of cerivastatin to M-23 andM-1 were about 2- to 2.5-fold higher by CYP2C8.4 than byCYP2C8.1 (Kaspera et al., 2010). The intrinsic clearanceof tanshinol borneol ester was not significantly differentbetweenCYP2C8.4 andCYP2C8.1 (Liu et al., 2010a). Onestudy suggests that the amino acid change in CYP2C8.4disrupts heme binding and results in an inactive protein(Singh et al., 2008). HLM heterozygous for CYP2C8*4showed a nonsignificant tendency for lower paclitaxel6a-hydroxylase activity (Bahadur et al., 2002). In silicopredictions suggest that the amino acid change inCYP2C8.4 is deleterious for CYP2C8 activity (Table 5).In vitro studies employing recombinant CYP2C8

have shown reduced paclitaxel 6a-hydroxylase activityin association with the p.Arg186Gln, p.Ala238Pro (*14),and p.Pro404Ala variants but no change in activity dueto the p.Gly171Ser, p.Ile223Met (*13), p.Lys247Arg,and p.Lys383Asn variants (Soyama et al., 2001; Hichiya

et al., 2005; Hanioka et al., 2010). In one study, thep.Ala238Pro and p.Ile223Met variants were associatedwith reduced amiodarone metabolism (Hanioka et al.,2011). One study demonstrated lack of CYP2C8 proteinexpression in association with the p.Glu274Ter (*11)nonsense variant (Yeo et al., 2011).

C. Effects on Drug Metabolism in Humans

In contrast to previous in vitro studies suggestinga reduced CYP2C8 activity in association with theCYP2C8*3 allele (Dai et al., 2001; Bahadur et al.,2002), the first pharmacokinetic study in humansshowed that the CYP2C8*3 allele was associated withreduced plasma concentrations of repaglinide (Niemiet al., 2003c). In this and later studies, individuals withtheCYP2C8*1/*3 genotype have had an approximately40–50% lower AUC of a subtherapeutic dose of repagli-nide than individuals with the CYP2C8*1/*1 genotype(Niemi et al., 2005b,c). However, this finding has notbeen fully replicated in studies with higher repaglinidedoses (Bidstrup et al., 2006; Tomalik-Scharte et al.,2011), suggesting that the effect of CYP2C8*3 allele onrepaglinide pharmacokinetics may be dose dependent.

Similarly to repaglinide, the CYP2C8*3 allele hasbeen associated with apparently increased clearance ofthe thiazolidinediones rosiglitazone and pioglitazone(Kirchheiner et al., 2006; Aquilante et al., 2008, 2013a;Tornio et al., 2008b). The AUCs of rosiglitazone or pioglit-azonehavebeenabout20–40% lower inCYP2C8*3 carriersthan in noncarriers, with an apparent gene-dose effect(Kirchheiner et al., 2006; Aquilante et al., 2008, 2013a;Tornio et al., 2008b). Furthermore, in a study in patientswith type 2 diabetes mellitus, the CYP2C8*3 allele hasbeen associated with significantly lower trough rosigli-tazone concentrations and an impaired lowering ofglycosylated hemoglobin (HbA1c) during rosiglitazonetreatment (Stage et al., 2013). In one study in AfricanAmerican subjects, the CYP2C8*2 allele had no impacton parent pioglitazone pharmacokinetics but was asso-ciated with impaired metabolism of pioglitazone to itsM3 metabolite (Aquilante et al., 2013c).

Although CYP2C8*2 has been associated with signif-icantly impaired amodiaquine metabolism in vitro(Parikh et al., 2007), the allele has not been clearlyassociated with amodiaquine efficacy or toxicity (Adjeiet al., 2008).However,more recent evidence suggests thatCYP2C8 genetic variability can influence the occurrenceof amodiaquine or chloroquine resistance in malariaparasites (Paganotti et al., 2011; Cavaco et al., 2013).

Studies in cancer patients have suggested that theCYP2C8*3 allele can slightly impair the clearance ofpaclitaxel (Henningsson et al., 2005; Bergmann et al.,2011). Some studies have also suggested that theCYP2C8*3 allele or other CYP2C8 variants may be riskfactors for paclitaxel-induced neurotoxicity or myelo-suppression and affect the benefit-to-risk ratio ofpaclitaxel therapy (Green et al., 2011; Leskelä et al.,

192 Backman et al.

2011; Hertz et al., 2012; Hertz et al., 2014; Lee et al.,2015). Further studies are required to clarify the roleof CYP2C8 genetic variants in affecting paclitaxelresponse.Some studies have reported significantly increased

plasma concentrations and apparently reduced clear-ance of racemic ibuprofen and its enantiomers inassociation with the CYP2C8*3 allele (Garcia-Martinet al., 2004; Martinez et al., 2005; Kara�zniewicz-Ładaet al., 2009). On the other hand, one study reportedenhanced clearance of R-ibuprofen in association withCYP2C8*3 (Lopez-Rodriguez et al., 2008). Becauseibuprofen is a substrate of CYP2C9, it is likely thatthe discrepancies are due to the strong linkage disequi-librium between CYP2C8*3 and CYP2C9*2 and re-duced ibuprofen clearance in CYP2C8*3 carriers is infact due to the CYP2C9*2 allele.Although CYP2C8 is not known to be involved in

bisphosphonate pharmacokinetics, an intronic SNV inCYP2C8 (rs1934951) has been associated with zole-dronic acid-induced osteonecrosis of the jaw in patientstreated for multiple myeloma (Sarasquete et al., 2008).In a more recent study, this SNV was associated withthe mandibular localization of bisphosphonate-inducedosteonecrosis (Balla et al., 2012). However, there was nosignificant relationship between the variant and thedevelopment of bisphosphonate-induced osteonecrosisof the jaw in men with prostate cancer (English et al.,2010) or in patients with multiple myeloma (Such et al.,2011). A meta-analysis found no significantly increasedsusceptibility to bisphosphonate-induced osteonecrosisof the jaw in rs1934951 carriers when all cancer typeswere pooled, but suggested a significant association inmultiple myeloma patients (Zhong et al., 2013).

V. In Vitro Inhibition and Induction ofCytochrome P450 2C8

A. Reversible Inhibition

1. Drugs That Act as Inhibitors of Cytochrome P4502C8. Several drugs, drug metabolites, and other com-pounds have been found to inhibit CYP2C8 activityreversibly in vitro (Tables 6 and 7). In an in vitroscreening of 209 commonly used drugs, 48 compoundsexhibited greater than 50% inhibition of recombinantCYP2C8 activity at an inhibitor concentration of 30 mM(Walsky et al., 2005a). Montelukast, candesartan cilex-etil, zafirlukast, clotrimazole, felodipine, and mometa-sone furoate inhibited CYP2C8 with concentrationssupporting half of the maximal inhibition (IC50) of#3 mM in recombinant CYP2C8 and HLM. In anotherstudy, the inhibition of CYP2C8 by montelukast wasfound to be competitive and selective, with reversibleinhibition constants (Ki) ranging from 0.0092 to 0.15 mM,depending on the protein concentration used in theincubation (Walsky et al., 2005b). However, despitetheir strong inhibitory effect on CYP2C8 in vitro,

neither montelukast nor zafirlukast affected the phar-macokinetics of CYP2C8 substrate drugs in vivo(Jaakkola et al., 2006b; Kajosaari et al., 2006b; Kimet al., 2007). The lack of in vivo effect is likely explainedby their extensive plasma protein binding (.99%)(FDA, 1998; Dekhuijzen and Koopmans, 2002). Alsothe inhibition of CYP2C8 by candesartran cilexetil(prodrug of candesartan), clotrimazole, and mometa-sone furoate are probably not clinically relevant. Theantifungal clotrimazole and anti-inflammatory mome-tasone furoate are topically applied and are thereforeunlikely to cause interactions because of low systemicconcentrations (Walsky et al., 2005a). In the systemiccirculation, candesartan cilexetil is cleaved to candesartan,and, consequently, the likelihood of a drug interactionelicited by its prodrug is low. Furthermore, predictionssuggested a relatively weak potential for drug-druginteractions due to CYP2C8 inhibition by felodipine. Nodrug interaction studies between felodipine andCYP2C8 substrates have been reported.

Trimethoprim, an antimicrobial agent, is a competi-tive inhibitor of CYP2C8 in vitro (Wen et al., 2002), witha Ki value typically around 10–30 mM in HLM (Table 6).The inhibition of CYP2C8 by trimethoprim seems to berather selective, because it does not inhibit CYP1A2,CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 atconcentrations below 100 mM. In healthy subjects, tri-methoprim has moderately increased the plasma expo-sure to several CYP2C8 substrate drugs (section VI.).

The flavonoid quercetin is one of the earliest in vitroinhibitors of CYP2C8 detected. In studies of paclitaxelmetabolism, it was observed that quercetin, unlikeCYP3A4 inhibitors, inhibited paclitaxel 6a-hydroxylation(Harris et al., 1994; Kumar et al., 1994). Because itwas shown that the 6a-hydroxylation of paclitaxel ismediated by CYP2C8, it was evident that quercetin isan inhibitor of this enzyme (Rahman et al., 1994).Quercetin inhibits CYP2C8 competitively with a Ki of0.03–20 mM (Table 7) and is classified as a "preferred"probe in vitro inhibitor of CYP2C8 by the FDA (http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm). However, quercetin is not selectivefor CYP2C8; it also inhibits CYP1A2, CYP2C9,CYP2C19, CYP2D6, and CYP3A4 with IC50 values of3.1–47 mM (Obach, 2000; Zou et al., 2002). In vivo,quercetin at steady state did not affect the pharmaco-kinetics of rosiglitazone (Kim et al., 2005a).

The lipid-lowering drug gemfibrozil is a moderate,direct competitive inhibitor of CYP2C8 in vitro (Wenet al., 2001; Prueksaritanont et al., 2002; Wang et al.,2002), with a Ki range between 9.3 and 270 mM(Table 6). Gemfibrozil also inhibits CYP2C9 andCYP2C19 with Ki values of 5.8 and 24 mM, respectively,and CYP1A2 with a Ki of 82 mM (Wen et al., 2001).Moreover, it inhibits several drug transporters in vitro,most notably OATP1B1 (lowest reported Ki = 4 mM)






TABLE

6Dru

gs,dr

ugmetab

olites,an

dsomeothe

rcompo

unds

that

actas

reve

rsible

CYP2C

8inhibitors

Inhibitor

Therap

euticUse

and/or

Dru

gClass

IC50

Ki

Mod

eof

Inhibition

Test

System

Marke

rRea

ctiona

I maxb

f ub

I/Kic

I u/K

icReferen

ces

mM

(mg/

ml)

mM

(mg/

ml)

mM

2-Oxo

-clopido

grel

Dru

gmetab

olite

33.9

rCYP2C

8DBF

Hag

iharaet

al.,20

084.1

rCYP2C

8Ceri-1

Floyd

etal.,20

124.2

rCYP2C

8Ceri-23

Floyd

etal.,20

1232

.0HLM

Amo

Tornio

etal.,20

142,4-Dichloroa

niline

Dru

gmetab

olite

99.4

HLM

Rosi-OH

Wuet

al.,20

144-Hyd

roxy

ospe

mifen

eDru

gmetab

olite

27.7

HLM

Amo

FDA,20

13i;Turp

einen

etal.,20

134’-H

ydroxy

ospe

mifen

eDru

gmetab

olite

7HLM

Amo

FDA,20

13i;Turp

einen

etal.,20

137-Epi-paclitaxe

lPaclitaxe

lep

imer

2.1

HLM

Pacli

Zhan

get

al.,20

09b

7-O-succinyl

macrolactin

AAntibiotic

20.5

HLM

Rosi-OH

Bae

etal.,20

1417

b-E

stradiol

(estradiol)

Hormon

alreplacem

ent

therap

y21

.5rC

YP2C

8Amo

Walsk

yet

al.,20

05a

6.6

Com

petitive

HLM

Amo

Van

denB

rink

etal.,20

1123

.8Com

petitive

HLM

Mon

teVan

denB

rink

etal.,20

1117

.7Com

petitive

HLM

Pacli

Van

denB

rink

etal.,20

118.9

Com

petitive

HLM

Rep

aVan

denB

rink

etal.,20

1123

.8Com

petitive

HLM

Rosi

Van

denB

rink

etal.,20

1119

HLM

Amo

Nirog

iet

al.,20

14Abiraterone

Anticancer,

CYP17

A1

inhibitor

1.6

HLM

n/a

0.65

0.00

20.81

,0.01

EMA,20

12a

Abirateroneacetate

Antican

cer,

CYP17

A1

inhibitor

1.3

HLM

n/a

EMA,20

12a

Acotiam

ide(Z-338

)Antidyspe

ptic,

acetylch

olinesterase

inhibitor

121

Com

petitive

HLM

DBF

Fur

utaet

al.,20

04,

Afatinib

Anticanc

er,PKI

94.83

HLM

Pacli

0.07

80.42

8,0.01

,0.01

Wan

get

al.,20

14a

Alisertib

(MLN82

37)

Antican

cer,

PKI

16.3

n/a

n/a

Pus

alka

ret

al.,20

14Alitretinoin(9-cis-retinoic

acid)

Anticanc

er,retinoid

17.6

20.2

HLM

Taz

a0.28

0.01

Attar

etal.,20

03

Amlodipine

Antihyp

ertens

ive,

CCB

10.7

rCYP2C

8Amo

0.03

190.07

,0.01

,0.01

Walsk

yet

al.,20

05a

6.4

rCYP2C

8Ceri-1

0.01

,0.01

Floyd

etal.,20

124.0

rCYP2C

8Ceri-23

0.02

,0.01

Floyd

etal.,20

129.4

HLM

Amo

,0.01

,0.01

Nirog

iet

al.,20

14Amod

iaqu

ine

Antimalarial

11.7

HLM

Mon

te0.04

7,0.01

Van

denB

rink

etal.,20

11.10

0HLM

Pacli

,0.01

Van

denB

rink

etal.,20

111.9

HLM

Rep

a0.02

Van

denBrinket

al.,20

1111

.0HLM

Rosi

,0.01

Van

denB

rink

etal.,20

11Anas

trozole

Anticanc

er,arom

atas

einhibitor

4810

Com

petitive

HLM

Tolbu

0.16

0.60

0.02

0.01

Grimm

andDyroff,19

97

Anidulafungin

Antifunga

l12

HLM

Amo

3.07

0.16

0.51

0.08

Dam

leet

al.,20

09Apo

morph

ine

Anti-Parkinson,do

pamine

agon

ist

1–10

rCYP2C

8DBF

4,0.01

8.00

,0.08

Salminen

etal.,20

11

Apr

emilas

tAntips

oriatic,

PDE4inhibitor

56.1

HLM

Pacli

0.76

40.32

0.03

,0.01

FDA,20

14e

Ataza

navir

Antiviral,pr

otea

seinhibitor

2.1

n/a

n/a

7.66

0.14

3.65

0.51

FDA,20

15b

Atorvas

tatin(acid,

parent)

Antihyp

erlipide

mic,

HMG-C

oAredu

ctas

einhibitor

38.4

15.9

Mixed

HLM

Pacli

0.09

80.02

,0.01

,0.01

Tornioet

al.,20

05

38.4

HLM

Pacli

,0.01

,0.01

Sak

aeda

etal.,20

0621

.9HLM

Amo

,0.01

,0.01

Jenk

inset

al.,20

1155

.7rC

YP2C

8Fluo

,0.01

,0.01

Sch

elleman

etal.,20

14Atorvas

tatinacyl-b- D

glucu

ronide(G

2)Dru

gmetab

olite

45HLM

Amo

Jenkinset

al.,20

11

(con

tinued

)

194 Backman et al.

TABLE

6—Con

tinued

Inhibitor

Therap

euticUse

and/or

Dru

gClass

IC50

Ki

Mod

eof

Inhibition

Test

System

Marke

rRea

ctiona

I maxb

f ub

I/Kic

I u/K

icReferen

ces

Atorvas

tatinlacton

eAntihyp

erlipide

mic,HMG-

CoA

redu

ctas

einhibitor

28.8

HLM

Pacli

Sak

aeda

etal.,20

06

Atraz

ine

Pesticide

31.3

HLM

Amo

Aba

sset

al.,20

09Axitinib

Antican

cer,

PKI

0.5

HLM

Pacli

0.16

0.01

0.32

,0.01

FDA,20

12f

0.11

HLM

Amo

2.90

0.03

Filpp

ula

etal.,20

140.17

HLM

Pacli

0.94

,0.01

Wan

get

al.,20

14a

AZD26

24Antips

ychotic,ne

urokinin-3

receptor

andtach

ykinin

receptor

3an

tago

nist

83.3

HLM

Amo

0.7

0.02

Liet

al.,20

10

Azilsartanmed

oxom

ilAntihyp

ertens

ive,

prod

rug

3.5

HLM

Pacli

FDA,20

11f

Belinostat

Anticanc

er,histone

deacetylas

einhibitor

100

HLM

n/a

100

0.07

12.00

0.14

FDA,20

14c

Belinostat3-ASBA

(M24

)Dru

gmetab

olite

49.1

HLM

n/a

FDA,20

14c

Belinostatacid

(M26

)Dru

gmetab

olite

22.1

HLM

n/a

FDA,20

14c

Belinostatam

ide

Dru

gmetab

olite

30.8

HLM

n/a

FDA,20

14c

BelinostatPX10

6507

Dru

gmetab

olite

13.8

HLM

n/a

FDA,20

14c

Ben

zbromaron

eAntihyp

eruricemic,XO

inhibitor

0.05

5Com

petitive

HLM

Amo

Van

denB

rink

etal.,20

11

0.38

Com

petitive

HLM

Mon

teVan

denB

rink

etal.,20

110.95

Com

petitive

HLM

Pacli

Van

denB

rink

etal.,20

110.15

Com

petitive

HLM

Rep

aVan

denB

rink

etal.,20

110.36

Com

petitive

HLM

Rosi

Van

denB

rink

etal.,20

11(2

)-N-3-ben

zyl-

phen

obarbital

Phe

noba

rbital

deriva

tive

34HLM

Pacli

Cai

etal.,20

04

Bezafibrate

Antihyp

erlipide

mic,PPARa

agon

ist

74HLM

Pacli

39.5

0.05

1.07

0.05

Fujinoet

al.,20

03a

9.7

Com

petitive

HLM

Pacli

4.07

0.20

Kajosaa

riet

al.,20

05a

Bisph

enol

ABisph

enol

97Non

compe

titive

rCYP2C

8Ami

Niw

aet

al.,20

00BTFM

gemfibrozil

Gem

fibrozilan

alog

13HLM

Amo

Jenk

inset

al.,20

11BTFM

gemfibrozilacyl-

b- D-glucu

ronide

Gem

fibrozilacyl-b-D-

gluc

uronide

analog

37HLM

Amo

Jenkinset

al.,20

11

Cab

ozan

tinib

Antican

cer,

PKI

5.0

rCYP2C

8n/a

3.27

,0.00

31.31

,0.01

FDA,20

12c

6.4

4.6

Non

compe

titive

HLM

Amo

0.71

,0.01

FDA,20

12c

3.8

4.6

Non

compe

titive

HLM

Amo

0.71

,0.01

Lacyet

al.,20

15;N

guye

net

al.,20

15Can

agliflozin

Antidiab

etic,SGLT2

inhibitor

75n/a

n/a

7.60

0.01

70.20

,0.01

FDA,20

13e

Can

agliflozin

glucu

ronide

(M7)

Dru

gmetab

olite

64n/a

Amo

FDA,20

13e

Can

desa

rtan

Antihyp

ertens

ive,

ARB

36.2

rCYP2C

8Amo

0.19

0.00

20.01

,0.01

Walsk

yet

al.,20

05a

Can

desa

rtan

cilexe

til

Antihyp

ertens

ive,

prod

rug

0.49

6rC

YP2C

8Amo

0.41

,0.01

1.65

0.02

Walsk

yet

al.,20

05a

3.04

HLM

Amo

0.27

,0.01

Walsk

yet

al.,20

05a

Carba

ryl

Pesticide

34.0

HLM

Amo

Aba

sset

al.,20

09Carve

dilol

Antihyp

ertens

ive

16.6

rCYP2C

8Amo

0.25

80.05

0.03

,0.01

Walsk

yet

al.,20

05a

Cefur

oxim

eax

etil

Antibiotic,pr

odru

g11

.1rC

YP2C

8Amo

19.6

0.67

3.53

2.37

Walsk

yet

al.,20

05a

Celecox

ibAnti-inflam

matory,

NSAID

15.9

rCYP2C

8Amo

1.85

0.03

0.23

,0.01

Walsk

yet

al.,20

05a

4.9

Com

petitive

HLM

Amo

0.38

0.01

Van

denB

rink

etal.,20

117.9

Com

petitive

HLM

Mon

te0.23

,0.01

Van

denB

rink

etal.,20

1154

.4Com

petitive

HLM

Pacli

0.03

,0.01

Van

denB

rink

etal.,20

113.1

Com

petitive

HLM

Rep

a0.60

0.02

Van

denB

rink

etal.,20

115.1

Com

petitive

HLM

Rosi

0.36

0.01

Van

denB

rink

etal.,20

119.9

rCYP2C

8Ceri-1

0.37

0.01

Floyd

etal.,20

125.4

rCYP2C

8Ceri-23

0.69

0.02

Floyd

etal.,20

12Ceritinib

Antican

cer,

PKI

0.6d

4.86

dHLM

Amo

1.81

0.02

80.37

0.01

FDA,20

14i

0.6d

HLM

Pacli

6.03

0.17

FDA,20

14i

(con

tinued

)


TABLE

6—Con

tinued

Inhibitor

Therap

euticUse

and/or

Dru

gClass

IC50

Ki

Mod

eof

Inhibition

Test

System

Marke

rRea

ctiona

I maxb

f ub

I/Kic

I u/K

icReferen

ces

Cerivas

tatin(acid,

parent)

Antihyp

erlipide

mic,HMG-

CoA

redu

ctas

einhibitor

34.4

HLM

Pacli

0.00

85,0.01

,0.01

,0.01

Fujinoet

al.,20

04

30.0

31.7

Mixed

HLM

Pacli

,0.01

,0.01

Tornioet

al.,20

0529

.8HLM

Pacli

,0.01

,0.01

Sak

aeda

etal.,20

064.2

Com

petitive

HLM

Amo

,0.01

,0.01

Van

denB

rink

etal.,20

114.6

Com

petitive

HLM

Mon

te,0.01

,0.01

Van

denB

rink

etal.,20

1177

.4Com

petitive

HLM

Pacli

,0.01

,0.01

Van

denB

rink

etal.,20

114.4

Com

petitive

HLM

Rep

a,0.01

,0.01

Van

denB

rink

etal.,20

1113

.4Com

petitive

HLM

Rosi

,0.01

,0.01

Van

denB

rink

etal.,20

11Cerivas

tatinlacton

eAntihyp

erlipide

mic,HMG-

CoA

redu

ctas

einhibitor

44.3

HLM

Pacli

Sak

aeda

etal.,20

06

Chlorp

yrifos

Pesticide

22.2

HLM

Amo

Aba

sset

al.,20

09Chlorp

romaz

ine

Antipsych

otic

20HLM

Amo

0.47

00.05

0.05

,0.01

Nirog

iet

al.,20

14Cim

etidine

Antiulcerative,

H2R

A25

0HLM

Pacli

120.81

0.10

0.08

Mon

sarrat

etal.,19

97Ciprofibrate

Antihyp

erlipide

mic,PPARa

agon

ist

441

HLM

Pacli

83.0

0.01

0.38

,0.01

Fujinoet

al.,20

03a

Clofazimine

Antilepr

ic14

.1HLM

Pacli

Shimok

awaet

al.,20

15Clopido

grel

Antithrombo

tic,

platelet

aggreg

ationinhibitor

10.2

rCYP2C

8Amo

0.06

0.02

0.01

,0.01

Walsk

yet

al.,20

05a

33.2

rCYP2C

8DBF

,0.01

,0.01

Hag

iharaet

al.,20

082.8

rCYP2C

8Ceri-1

0.04

,0.01

Floyd

etal.,20

123.4

rCYP2C

8Ceri-23

0.04

,0.01

Floyd

etal.,20

1253

.6HLM

Amo

,0.01

,0.01

Tornioet

al.,20

14Clopido

grel

carbox

ylic

acid

Dru

gmetab

olite

.50

.0rC

YP2C

8DBF

Hag

iharaet

al.,20

0810

7rC

YP2C

8Ceri-1

Floyd

etal.,20

1213

6rC

YP2C

8Ceri-23

Floyd

etal.,20

12Clopido

grel

active

metab

olite

Dru

gmetab

olite

.50

.0rC

YP2C

8DBF

Hag

iharaet

al.,20

08

Clotrim

azole

Antifung

al2.5

Non

compe

titive

rCYP2C

8Torse

0.00

8,0.01

Onget

al.,20

000.72

5rC

YP2C

8Amo

0.02

Walsk

yet

al.,20

05a

0.77

6HLM

Amo

0.02

Walsk

yet

al.,20

05a

0.12

Com

petitive

HLM

Amo

0.07

Van

denB

rink

etal.,20

110.27

Com

petitive

HLM

Mon

te0.03

Van

denB

rink

etal.,20

110.22

Com

petitive

HLM

Pacli

0.04

Van

denB

rink

etal.,20

110.19

Com

petitive

HLM

Rep

a0.04

Van

denB

rink

etal.,20

111.9

Com

petitive

HLM

Rosi

,0.01

Van

denB

rink

etal.,20

110.80

3HLM

Pacli

0.02

Lee

etal.,20

12a

Cob

icistat

Antiviral,ph

armacok

inetic

inhibitor

30.1

HLM

Pacli

2.38

0.03

0.16

,0.01

FDA,20

12j

CP-778

875

Antihyp

erlipide

mic,PPARa

agon

ist

1.83

HLM

Amo

Kalgu

tkar

etal.,20

13

Cyclosp

orine

Immun

osupp

ressan

t,calcineu

rininhibitor

79rC

YP2C

8Pacli

1.11

0.07

0.03

,0.01

Yoshida

etal.,20

12

CYP3cide(PF-049

8151

7)Pharmacok

inetic

inhibitor

78HLM

Pacli

Walsk

yet

al.,20

12Dab

rafenib

Antican

cer,

PKI

7.7–

8.2

HLM

Rosi

2.85

0.00

30.74

,0.01

Law

renc

eet

al.,20

14Dalcetrap

ibAntihyp

erlipide

mic,

cholesterylester

tran

sfer

proteininhibitor

1.5

HLM

Pacli

9.70

12.93

Derks

etal.,20

09

Dan

azol

Hyp

oestroge

nic,

hype

rand

roge

nic,

ethisteron

ede

riva

tive

1.95

HLM

Pacli

0.21

0.22

Lee

etal.,20

12a

Das

abuvir(A

BT-333

)Antiviral,NSB5inhibitor

;17

Com

petitive

n/a

n/a

2.09

0.00

5;0.25

,0.01

FDA,20

14k

Das

atinib

Anticanc

er,PKI

123.6

HLM

Pacli

0.13

0.04

0.04

,0.01

FDA,20

06a

38.6

HLM

Pacli

,0.01

,0.01

Kim

etal.,20

13b

6.31

HLM

Pacli

0.02

,0.01

Wan

get

al.,20

14a

(con

tinued

)

196 Backman et al.

TABLE

6—Con

tinued

Inhibitor

Therap

euticUse

and/or

Dru

gClass

IC50

Ki

Mod

eof

Inhibition

Test

System

Marke

rRea

ctiona

I maxb

f ub

I/Kic

I u/K

icReferen

ces

N-deb

utyldroned

aron

e(SR35

021)

Dru

gmetab

olite

24.4

36.6

Non

compe

titive

HLM

Pacli

FDA,20

09a

N-deethyl

sunitinib

(SU12

662)

Dru

gmetab

olite

52HLM

Pacli

FDA,20

06b

N-dem

ethylim

atinib

Dru

gmetab

olite

99HLM

Pacli

FDA,20

0131

.312

.8Mixed

HLM

Amo

Filpp

ula

etal.,20

12N-dem

ethyltoremifen

eDru

gmetab

olite

2.1

HLM

Pacli

Kim

etal.,20

11b

Deferas

irox

Antido

te,iron

chelating

agen

t10

0HLM

Pacli

0.46

0.01

,0.01

,0.01

FDA,20

05a

Deferas

irox

metab

olite

CGP82

813A

Dru

gmetab

olite

160

HLM

Pacli

FDA,20

05a

Dex

amethas

one

Anti-inflam

matory,

glucu

corticoid

12.0

rCYP2C

8Amo

8.15

1.36

Walsk

yet

al.,20

05a

Diclofena

cAnti-inflammatory,

NSAID

54HLM

Amo

6.28

,0.00

50.23

,0.01

Jenk

inset

al.,20

11Diclofena

cacyl

gluc

uron

ide

Dru

gmetab

olite

14HLM

Amo

Jenk

inset

al.,20

11Diethyldithiocarbam

ate

Alcoh

olic

detergen

t12

9.5

rCYP2C

8Dia

Sai

etal.,20

0046

4.1

rCYP2C

8Phen

aSai

etal.,20

00Diethylstilbe

strol

Syn

thetic

estrog

en8.0

Com

petitive

HLM

Pacli

Quet

al.,20

11Diltiaz

emAntihyp

ertens

ive,

CCB

25rC

YP2C

8Ceri-1

0.33

50.22

0.03

,0.01

Floyd

etal.,20

1212

4rC

YP2C

8Ceri-23

,0.01

,0.01

Floyd

etal.,20

12Dox

orubicin

Anticanc

er2

HLM

Pacli

1.63

0.24

1.63

0.39

Mon

sarrat

etal.,19

9764

.8Com

petitive

HLM

Pacli

0.03

,0.01

Bun

etal.,20

0390

Non

compe

titive

HLM

Luc

i0.02

,0.01

Mas

eket

al.,20

11Dulox

etine

Antide

pressa

nt,SNRI

180

HLM

Pacli

0.07

90.05

,0.01

,0.01

FDA,20

08b

60HLM

Amo

,0.01

,0.01

Paris

etal.,20

09Efavirenz

Antiviral,NNRTI

4.0

rCYP2C

8Amo

12.6

0.00

56.30

0.03

Parikhet

al.,20

076.05

Com

petitive

rCYP2C

8Amo

2.08

0.01

Xuan

dDesta,20

134.78

Com

petitive

HLM

Amo

2.64

0.01

Xuan

dDesta,20

13Eltrombo

pag

Antihem

orrh

agic,c-mpl

receptor

agon

ist

24.8

HLM

Pacli

29,0.01

2.34

0.02

FDA,20

08c

Enz

alutam

ide

Antican

cer,

antian

drog

en10

5.5

Mixed

HLM

Amo

35.7

0.02

6.50

0.13

FDA,20

12k

Enza

lutamideM1

Dru

gmetab

olite

20HLM

Amo

FDA,20

12k

Enza

lutamideM2

Dru

gmetab

olite

28HLM

Amo

FDA,20

12k

Erlotinib

Anticancer,

PKI

6.17

5.8

Com

petitive

HLM

Pacli

6.06

0.10

1.05

0.10

Don

get

al.,20

119.5

HLM

Pacli

1.28

0.13

Kim

etal.,20

13b

4.02

HLM

Pacli

1.51

0.15

Wan

get

al.,20

14a

Esomep

razole

(S-

omep

razole)

Antiulcerative,

PPI

31.0

HLM

Amo

4.5

0.05

0.29

0.02

Zvy

agaet

al.,20

12

Ethionam

ide

Antitube

rculosis

110

HLM

Pacli

12.99

0.70

0.24

0.17

Shimok

awaet

al.,20

15Etrav

irine

Antiviral,NNRTI

19.6

Non

compe

titive

HLM

Pacli

2.2

0.01

0.11

,0.01

FDA,20

08a

Exe

mestane

Anticanc

er,arom

atas

einhibitor

13.5

rCYP2C

8Amo

0.06

00.10

,0.01

,0.01

Walsk

yet

al.,20

05a

Feb

uxo

stat

Antihyp

erur

icem

ic,XO

inhibitor

20n/a

n/a

16.78

0.00

70.84

,0.01

Naiket

al.,20

12

Felod

ipine

Antihyp

ertens

ive,

CCB

0.72

6rC

YP2C

8Amo

0.00

730.00

40.02

,0.01

Walsk

yet

al.,20

05a

1.20

HLM

Amo

0.01

,0.01

Walsk

yet

al.,20

05a

Fen

itrothion

Pesticide

4.3

HLM

Amo

Aba

sset

al.,20

09Fen

ofibrate

Antihyp

erlipide

mic,

PPARaag

onist

288

HLM

Pacli

23.83

,0.01

0.17

,0.01

Fujinoet

al.,20

03a

92.6

Com

petitive

HLM

Pacli

0.26

,0.01

Kajosaa

riet

al.,20

05a

2.39

rCYP2C

8Amo

19.94

0.20

Walsk

yet

al.,20

05a

4.8

rCYP2C

8Fluo

9.93

0.10

Sch

elleman

etal.,20

14Fluox

ymesterone

Andr

ogen

ic,3-ox

oand

rosten

(4)de

riva

tive

16rC

YP2C

8Ceri-1

Floyd

etal.,20

12

16rC

YP2C

8Ceri-23

Floyd

etal.,20

12 (con

tinued

)


TABLE

6—Con

tinued

Inhibitor

Therap

euticUse

and/or

Dru

gClass

IC50

Ki

Mod

eof

Inhibition

Test

System

Marke

rRea

ctiona

I maxb

f ub

I/Kic

I u/K

icReferen

ces

Fluticasone

Anti-inflam

matory,

gluc

ocorticoid

0.58

HLM

Pacli

0.00

023

0.01

,0.01

,0.01

FDA,20

13c

FluticasoneM10

metab

olite

Dru

gmetab

olite

80HLM

Pacli

FDA,20

13c

Fluva

statin

(acid,

parent)

Antihyp

erlipide

mic,HMG-

CoA

redu

ctas

einhibitor

20HLM

Pacli

0.46

10.01

0.05

,0.01

Fisch

eret

al.,19

99

36.7

18.9

Mixed

HLM

Pacli

0.02

,0.01

Tornioet

al.,20

0515

.1rC

YP2C

8Amo

0.06

,0.01

Walsk

yet

al.,20

05a

70.2

HLM

Pacli

0.01

,0.01

Sak

aeda

etal.,20

06Fluva

statin

lacton

eAntihyp

erlipide

mic,HMG-

CoA

redu

ctas

einhibitor

55.4

HLM

Pacli

Sak

aeda

etal.,20

06

Gefitinib

Anticanc

er,PKI

31.0

HLM

Pacli

0.8

0.10

0.05

,0.01

Kim

etal.,20

13b

12.3

HLM

Amo

0.13

0.01

Filpp

ulaet

al.,20

148.69

HLM

Pacli

0.09

,0.01

Wan

get

al.,20

14a

Gem

fibrozil

Antihyp

erlipide

mic,PPARa

agon

ist

49Hep

Ceri-23

100

,0.03

4.08

0.12

Pru

eksa

ritano

ntet

al.,20

0287

Com

petitive

HLM

Pacli

1.15

0.03

Pru

eksa

ritano

ntet

al.,20

0278

rCYP2C

8Ceri-1

2.56

0.08

Wan

get

al.,20

0268

rCYP2C

8Ceri-23

2.94

0.09

Wan

get

al.,20

02.25

027

3Com

petitive

HLM

Ceri-1

,0.37

,0.01

Wan

get

al.,20

0295

69Com

petitive

HLM

Ceri-23

1.45

0.04

Wan

get

al.,20

0291

75–76

Com

petitive

HLM

Pacli

1.33

0.04

Wan

get

al.,20

0248

Mixed

HLM

Pacli

4.17

0.13

Fujinoet

al.,20

03a

55.4

Mixed

HLM

Pacli

1.81

0.05

Fujinoet

al.,20

03b

36.8

rCYP2C

8Ceri-1

5.44

0.16

Shitara

etal.,20

0429

.7rC

YP2C

8Ceri-23

6.73

0.20

Shitara

etal.,20

0411

969

.0Non

compe

titive

HLM

Rosi-OH

1.45

0.04

Hru

skaet

al.,20

0530

.4Com

petitive

HLM

Pacli

3.29

0.10

Kajosaa

riet

al.,20

05a

75.6

rCYP2C

8Amo

2.65

0.08

Walsk

yet

al.,20

05a

59HLM

Pio

3.39

0.10

Jaak

kola

etal.,20

06c

120

HLM

Pacli

1.67

0.05

Ogilvie

etal.,20

0610

7HLM

Mon

te1.87

0.06

Karon

enet

al.,20

1063

HLM

Mon

te-4

3.18

0.10

Karon

enet

al.,20

1012

0HLM

Amo

1.67

0.05

Jenkinset

al.,20

1110

.2Com

petitive

HLM

Amo

9.80

0.29

Van

denB

rink

etal.,20

1113

.5Com

petitive

HLM

Mon

te7.41

0.22

Van

denB

rink

etal.,20

11.10

0Com

petitive

HLM

Pacli

1.00

0.03

Van

denB

rink

etal.,20

119.3

Com

petitive

HLM

Rep

a10

.75

0.32

Van

denB

rink

etal.,20

1136

.1Com

petitive

HLM

Rosi

2.77

0.08

Van

denB

rink

etal.,20

1114

rCYP2C

8Ceri-23

7.14

0.21

Floyd

etal.,20

12Gen

istein

Anticancer,

PKI

2.5

HLM

Pacli

Burn

ettet

al.,20

11Glipizide

Antidiabe

tic,

sulfon

ylurea

338.2

rCYP2C

8Fluo

1.04

0.01

6,0.01

,0.01

Sch

elleman

etal.,20

14Glybu

ride

(glibe

nclam

ide)

Antidiab

etic,su

lfon

ylur

ea10

.8rC

YP2C

8Amo

0.21

40.00

20.04

,0.01

Walsk

yet

al.,20

05a

4.3

rCYP2C

8Ceri-1

0.10

,0.01

Floyd

etal.,20

126.7

rCYP2C

8Ceri-23

0.06

,0.01

Floyd

etal.,20

12Glyph

osate

Pesticide

82.0

HLM

Amo

Aba

sset

al.,20

09Hyd

roxy

methyl-iva

caftor

(M1)

Dru

gmetab

olite

17.7

0.39

Com

petitive

HLM

Amo

FDA,20

12g

Ibru

tinib

Anticanc

er,PKI

12.03

HLM

Pacli

0.37

0.12

70.03

,0.01

FDA,20

13d

Ibru

tinibmetab

olitePCI-

4522

7Dru

gmetab

olite

(7.84)

HLM

Pacli

FDA,20

13d

Iclapr

imAntibiotic

(91.5)

rCYP2C

8n/a

Hallet

al.,(200

7)ID

9515

51Acotiam

idean

alog

17HLM

DBF

Furu

taet

al.,20

04Idelalisib

Anticanc

er,PKI

13HLM

Pacli

4.6

,0.16

0.71

0.11

FDA,20

14h

(con

tinued

)

198 Backman et al.

TABLE

6—Con

tinued

Inhibitor

Therap

euticUse

and/or

Dru

gClass

IC50

Ki

Mod

eof

Inhibition

Test

System

Marke

rRea

ctiona

I maxb

f ub

I/Kic

I u/K

icReferen

ces

Idelalisib

metab

oliteGS-

5631

17Dru

gmetab

olite

39.8

HLM

Pacli

9.4

,0.12

0.47

0.06

FDA,20

14h

Imatinib

Anticancer,

PKI

15.7

8.4

Mixed

HLM

Amo

5.27

0.05

0.63

0.03

Filpp

ulaet

al.,20

1225

.9HLM

Pacli

0.41

0.02

Kim

etal.,20

13b

11.28

HLM

Pacli

0.47

0.02

Wan

get

al.,20

14a

Inda

caterol

Antiobs

truc

tive

,LABA

30HLM

Pacli

0.00

125

0.04

9,0.01

,0.01

FDA,20

11a

Indiplon

Sed

ative,

GABAA

receptor

mod

ulator

3015

HLM

Pacli

Mad

anet

al.,20

07

Indo

methacin

Anti-inflam

matory,

NSAID

88HLM

Amo

6.7

0.10

0.15

0.02

Jenk

inset

al.,20

11In

domethacin

acyl-b-D

-glucu

ronide

Dru

gmetab

olite

26HLM

Amo

Jenkinset

al.,20

11

Ipriflav

oneM1

Dru

gmetab

olite

9.9

HLM

Pacli

Moonet

al.,20

07Ipriflav

oneM2

Dru

gmetab

olite

10.2

HLM

Pacli

Moonet

al.,20

07Ipriflav

oneM4

Dru

gmetab

olite

31.8

HLM

Pacli

Moonet

al.,20

07Ipriflav

oneM5

Dru

gmetab

olite

2.5

HLM

Pacli

Moonet

al.,20

07Irbe

sartan

Antihyp

ertens

ive,

ARB

9.73

rCYP2C

8Amo

3.0

0.10

0.62

0.06

Walsk

yet

al.,20

05a

18rC

YP2C

8Ceri-1

0.33

0.03

Floyd

etal.,20

1216

rCYP2C

8Ceri-23

0.38

0.04

Floyd

etal.,20

12Isotretino

in(13-cis-retinoic

acid)

Antiacne

,retinoid

15.1

66.2

HLM

Taz

a0.69

,0.01

0.01

,0.01

Attar

etal.,20

03

Isradipine

Antihyp

ertens

ive,

CCB

5.00

HLM

Pacli

0.03

00.03

0.01

,0.01

Lee

etal.,20

12a

Itracona

zole

Antifunga

l31

rCYP2C

8Pacli

0.9

0.00

20.06

,0.01

Yoshida

etal.,20

12Ivacaftor

Antifibrotic

3.8

3.4

Mixed

HLM

Amo

13.89

,0.02

4.09

0.08

FDA,20

12g

Ivacaftormetab

olite(M

6)Dru

gmetab

olite

63.1

HLM

Amo

FDA,20

12g

Ketocon

azole

Antifung

al25

HLM

Pacli

3.2

0.01

0.26

,0.01

Mon

sarrat

etal.,19

972.5

Non

compe

titive

rCYP2C

8Torse

1.28

0.01

Ong

etal.,20

004.0

rCYP2C

8Dia

1.60

0.02

Sai

etal.,20

008.9

rCYP2C

8Phen

a0.72

,0.01

Sai

etal.,20

006-9

HLM

Pacli

1.07

0.01

Dierk

set

al.,20

0111

.8Non

compe

titive

HLM

Pacli

0.27

,0.01

Bun

etal.,20

0387

.7HLM

Amo

0.07

,0.01

Tur

peinen

etal.,20

055.51

rCYP2C

8Amo

1.16

0.01

Walsk

yet

al.,20

05a

4rC

YP2C

8Amo

1.60

0.02

O’Don

nellet

al.,20

072.45

HLM

Pacli

2.61

0.03

Lee

etal.,20

12a

1.7

HLM

Amo

3.77

0.04

Nirog

iet

al.,20

15Ketop

rofenacyl-b- D-

glucu

ronide

Dru

gmetab

olite

26HLM

Amo

Jenkinset

al.,20

11

KR-325

70Antiarrh

ythmic

30HLM

Pacli

Kim

etal.,20

06KR-604

36Antiulcerative,

PPI

30HLM

Pacli

Jiet

al.,20

05Lan

sopr

azole

Antiulcerative,

PPI

55rC

YP2C

8Ceri-1

0.67

10.03

0.02

,0.01

Floyd

etal.,20

1219

rCYP2C

8Ceri-23

0.07

,0.01

Floyd

etal.,20

125.75

HLM

Pacli

0.23

,0.01

Lee

etal.,20

12a

Lap

atinib

Antican

cer,

PKI

0.60

Com

petitive

HLM

Pacli

4.2

,0.01

7.00

,0.07

FDA,20

07e

1.43

HLM

Pacli

2.94

,0.03

Wan

get

al.,20

14a

Larop

iprant

Antias

thmatic,PGD2

receptor

antago

nist

6.5

n/a

n/a

Sch

wartz

etal.,20

09

Larom

ustine

(VNP40

101M

)Antican

cer,

alky

latingag

ent

.75

0Non

compe

titive

HLM

Amo

Nas

saret

al.,20

09

Las

ofox

ifen

eAntiosteopo

rotic,

SERM

8.1

HLM

Amo

0.00

50,0.01

Molleret

al.,20

06Len

vatinib

Antican

cer,

PKI

10.1

10.1

HLM

Pacli

1.54

60.02

0.15

,0.01

FDA,20

15a

Lestaurtinib

(CEP-701

)Anticanc

er,PKI

9.5

HLM

Amo

Filpp

ulaet

al.,20

14Lev

othyrox

ine

Hormon

alreplacem

ent

therap

y3.30

rCYP2C

8Amo

Walsk

yet

al.,20

05a

5.4

rCYP2C

8Ceri-1

Floyd

etal.,20

124.6

rCYP2C

8Ceri-23

Floyd

etal.,20

12 (con

tinued

)


TABLE

6—Con

tinued

Inhibitor

Therap

euticUse

and/or

Dru

gClass

IC50

Ki

Mod

eof

Inhibition

Test

System

Marke

rRea

ctiona

I maxb

f ub

I/Kic

I u/K

icReferen

ces

Lop

eram

ide

Antidiarrh

eal,op

ioid

24HLM

Amo

0.00

42,0.01

Nirog

iet

al.,20

14Lop

inav

irAntiviral,pr

otea

seinhibitor

4.1

rCYP2C

8Amo

15.6

0.02

7.61

0.15

Parikhet

al.,20

07Loratad

ine

Antihistamine

3.36

rCYP2C

8Amo

0.00

880.03

,0.01

,0.01

Walsk

yet

al.,20

05a

2.95

HLM

Pacli

,0.01

,0.01

Lee

etal.,20

12a

Lorcaserin

Antiob

esity,

5-HT2Creceptor

agon

ist

.20

0HLM

Pacli

0.43

40.30

,0.01

,0.01

FDA,20

12b

Lorcaserinsu

lfam

ate(M

1)Dru

gmetab

olite

.20

0HLM

Pacli

FDA,20

12b

Losartan

Antihyp

ertens

ive,

ARB

12.9

rCYP2C

8Amo

0.64

0.01

30.10

,0.01

Walsk

yet

al.,20

05a

40.7

Com

petitive

rCYP2C

8Pacli

0.02

,0.01

Muka

iet

al.,20

14Lov

astatin(lactone

,pa

rent)

Antihyp

erlipide

mic,HMG-

CoA

redu

ctas

einhibitor

14.7

8.4

Mixed

HLM

Pacli

0.10

00.05

0.01

,0.01

Tornioet

al.,20

05

9.10

rCYP2C

8Amo

0.02

,0.01

Walsk

yet

al.,20

05a

79.9

HLM

Pacli

,0.01

,0.01

Sak

aeda

etal.,20

065.6

Com

petitive

HLM

Amo

0.02

,0.01

Van

denB

rink

etal.,20

119.3

Com

petitive

HLM

Mon

te0.01

,0.01

Van

denB

rink

etal.,20

1118

.8Com

petitive

HLM

Pacli

,0.01

,0.01

Van

denB

rink

etal.,20

112.8

Com

petitive

HLM

Rep

a0.04

,0.01

Van

denB

rink

etal.,20

114.2

Com

petitive

HLM

Rosi

0.02

,0.01

Van

denB

rink

etal.,20

1127

.5rC

YP2C

8Fluo

,0.01

,0.01

Sch

elleman

etal.,20

14Lov

astatinacid

Antihyp

erlipide

mic,HMG-

CoA

redu

ctas

einhibitor

54.9

48.9

Mixed

HLM

Pacli

0.01

10.05

,0.01

,0.01

Tornioet

al.,20

05

74.6

HLM

Pacli

,0.01

,0.01

Sak

aeda

etal.,20

06Maciten

tan

Antihyp

ertens

ive,

ERA

21HLM

Pacli

0.29

,0.01

0.03

,0.01

FDA,20

13k

Maciten

tanmetab

oliteM6

(ACT-132

577)

Dru

gmetab

olite

23HLM

Pacli

FDA,20

13k

Macrolactin

AAntibiotic

26.4

HLM

Rosi-OH

Bae

etal.,20

14Malathion

Pesticide

31.0

HLM

Amo

Aba

sset

al.,20

09Med

roxy

prog

esterone

Proge

stin

4.79

rCYP2C

8Amo

0.12

30.14

0.05

,0.01

Walsk

yet

al.,20

05a

0.76

Com

petitive

HLM

Amo

0.16

0.02

Van

denB

rink

etal.,20

117.5

Com

petitive

HLM

Mon

te0.02

,0.01

Van

denB

rink

etal.,20

118.2

Com

petitive

HLM

Pacli

0.02

,0.01

Van

denB

rink

etal.,20

111.9

Com

petitive

HLM

Rep

a0.07

,0.01

Van

denB

rink

etal.,20

116.6

Com

petitive

HLM

Rosi

0.02

,0.01

Van

denB

rink

etal.,20

11Mefen

amic

acid

Anti-inflammatory,

NSAID

14.9

HLM

Amo

41.44

,0.10

5.56

0.56

Jenk

inset

al.,20

11Mefen

amic

acyl-b- D-

gluc

uron

ide

Dru

gmetab

olite

8.5

HLM

Amo

Jenkinset

al.,20

11

Mertans

ine(D

M1)

Antibo

dy-dru

glink

er11

Com

petitive

HLM

Pacli

Dav

iset

al.,20

12Methox

salen(8-

methox

ypsoralen)

Antipsoriatic

;10

HLM

Pacli

2.36

;0.47

Dierk

set

al.,20

01

Methyl

belinostat

Dru

gmetab

olite

13.8

HLM

n/a

FDA,20

14c

Methy

lpredn

isolon

eAnti-inflammatory,

gluc

ucorticoid

25.4

rCYP2C

8Amo

0.47

50.22

0.04

,0.01

Walsk

yet

al.,20

05a

Midaz

olam

Sed

ative,

benz

odiazepine

18Non

compe

titive

rCYP2C

8Torse

0.34

0.02

0.02

,0.01

Onget

al.,20

0012

.4rC

YP2C

8Amo

0.06

,0.01

Walsk

yet

al.,20

05a

MMB4DMS

Antido

te,ch

olinergicag

onist

82.9

126

Non

compe

titive

rCYP2C

8Luc

iHon

get

al.,20

13Mom

etas

onefuroate

Anti-inflam

matory,

glucu

corticoid

0.81

3rC

YP2C

8Amo

0.00

012

0.02

,0.01

,0.01

Walsk

yet

al.,20

05a

0.32

7HLM

Amo

,0.01

,0.01

Walsk

yet

al.,20

05a

Mon

teluka

stAntias

thmatic,LTRA

0.00

922

rCYP2C

8Amo

0.89

,0.01

193.06

1.93

Walsk

yet

al.,20

05a

0.01

96HLM

Amo

90.82

0.91

Walsk

yet

al.,20

05a

0.00

92Com

petitive

rCYP2C

8Amo

96.74

0.97

Walsk

yet

al.,20

05b

0.01

9Com

petitive

rCYP2C

8Rosi

46.84

0.47

Walsk

yet

al.,20

05b

0.02

0–2.0

0.01

4Com

petitive

HLM

Amo

63.57

0.64

Walsk

yet

al.,20

05b

0.15

Com

petitive

HLM

Pacli

5.93

0.06

Walsk

yet

al.,20

05b

0.11

Com

petitive

HLM

Rosi

8.09

0.08

Walsk

yet

al.,20

05b

(con

tinued

)

200 Backman et al.

TABLE

6—Con

tinued

Inhibitor

Therap

euticUse

and/or

Dru

gClass

IC50

Ki

Mod

eof

Inhibition

Test

System

Marke

rRea

ctiona

I maxb

f ub

I/Kic

I u/K

icReferen

ces

0.18

HLM

Pio

9.89

0.10

Jaak

kola

etal.,20

06c

0.00

9–0.01

rCYP2C

8Amo

197.78

1.98

O’Don

nellet

al.,20

070.02

20.01

3HLM

Amo

68.46

0.69

Perloffet

al.,20

090.00

81Com

petitive

HLM

Amo

109.88

1.10

Van

denB

rink

etal.,20

110.02

6Com

petitive

HLM

Pacli

34.23

0.34

Van

denB

rink

etal.,20

110.01

6Com

petitive

HLM

Rep

a55

.63

0.56

Van

denB

rink

etal.,20

110.21

Com

petitive

HLM

Rosi

4.24

0.04

Van

denB

rink

etal.,20

111.2

rCYP2C

8Ceri-1

1.48

0.02

Floyd

etal.,20

120.02

rCYP2C

8Ceri-23

89.00

0.89

Floyd

etal.,20

120.05

–0.10

HLM

Amo

35.60

0.36

Kozak

aiet

al.,20

120.14

Com

petitive

HLM

Pacli

6.36

0.06

Kim

etal.,20

13b

0.16

Com

petitive

HLM

Amo

5.56

0.06

Kim

etal.,20

13b

2.67

HLM

Pacli

0.67

,0.01

Zhen

get

al.,20

130.27

n/a

n/a

6.59

0.07

Korzekw

a,20

1415

9Hep

Amo

0.01

,0.01

Kosugi

etal.,20

142.9

HLM

Rosi-OH

0.61

,0.01

Zhen

get

al.,20

140.10

1HLM

Pacli

17.62

0.18

FDA,20

14j

0.14

HLM

Amo

12.71

0.13

FDA,20

14j

0.01

0–0.75

HLM

Amo

178.00

1.78

Nirog

iet

al.,20

15Neb

ivolol

Antihyp

ertens

ive,

b1

receptor

blocke

r55

Non

compe

titive

HLM

Pacli

3.65

0.08

870.07

,0.01

FDA,20

07a

Nefaz

odon

eAntide

pressa

nt

23.2

rCYP2C

8Amo

4.70

,0.01

0.41

,0.01

Walsk

yet

al.,20

05a

Netupitant

Antiem

etic

50.43

HLM

Pacli

0.75

0.00

50.03

,0.01

FDA,20

14b

Netupitant

hydr

oxylation

metab

oliteM3

Dru

gmetab

olite

26.95

HLM

Pacli

FDA,20

14b

Netupitant

N-

demethy

lation

metab

oliteM1

Dru

gmetab

olite

4.74

HLM

Pacli

FDA,20

14b

Nicardipine

Antihyp

ertens

ive,

CCB

7.1

HLM

Pacli

0.17

0.02

0.02

,0.01

Nak

amura

etal.,20

051.56

HLM

Pacli

0.22

,0.01

Lee

etal.,20

12a

Nifed

ipine

Antihyp

ertens

ive,

CCB

9.66

rCYP2C

8Amo

0.14

0.04

0.03

,0.01

Walsk

yet

al.,20

05a

20-23

rCYP2C

8Amo

0.01

,0.01

O’Don

nellet

al.,20

0713

.53

rCYP2C

8Pacli

0.02

,0.01

Gao

etal.,20

102.4

Com

petitive

HLM

Amo

0.06

,0.01

Van

denB

rink

etal.,20

116.3

Com

petitive

HLM

Mon

te0.02

,0.01

Van

denB

rink

etal.,20

119.5

Com

petitive

HLM

Pacli

0.02

,0.01

Van

denB

rink

etal.,20

111.5

Com

petitive

HLM

Rep

a0.09

,0.01

Van

denB

rink

etal.,20

115.8

Com

petitive

HLM

Rosi

0.02

,0.01

Van

denB

rink

etal.,20

113.5

HLM

Amo

0.08

,0.01

Nirog

iet

al.,20

14Nilotinib

Anticanc

er,PKI

,1

0.23

6Com

petitive

HLM

Pacli

4.3

0.02

18.22

0.36

FDA,20

07c

0.61

Com

petitive

rCYP2C

8Amo

7.04

0.14

Kim

etal.,20

13b

0.10

Com

petitive

rCYP2C

8Pacli

43.00

0.86

Kim

etal.,20

13b

0.7

0.15

Com

petitive

HLM

Amo

28.67

0.53

Kim

etal.,20

13b

0.4

0.9

Com

petitive

HLM

Pacli

4.78

0.10

Kim

etal.,20

13b

7.5

HLM

Rosi-OH

1.15

0.02

Kim

etal.,20

13b

0.10

HLM

Pacli

43.00

0.86

Wan

get

al.,20

14a

Ninteda

nib

Anticancer,

PKI

.50

HLM

Pacli

0.02

80.02

2,0.01

,0.01

FDA,20

14d

Nystatin

Antifun

gal

12.7

rCYP2C

8Amo

Walsk

yet

al.,20

05a

Ombitasvir

(ABT-267

)Antiviral,NS5A

inhibitor

7.4

n/a

n/a

0.07

0,0.01

0.02

,0.01

FDA,20

14k

Orp

henad

rine

Mus

clerelaxa

nt

278.8

rCYP2C

8Dia

Sai

etal.,20

0024

9.1

rCYP2C

8Phen

aSai

etal.,20

0026

5HLM

Amo

Nirog

iet

al.,20

15Orteron

el(TAK-700

)Antican

cer,

antian

drog

en27

.7HLM

n/a

Luet

al.,20

12Osp

emifen

eAntidy

spareu

nia,SERM

36.4

HLM

Amo

3.16

,0.01

0.17

,0.01

FDA,20

13i;Turp

einen

etal.,20

13

(con

tinued

)


TABLE

6—Con

tinued

Inhibitor

Therap

euticUse

and/or

Dru

gClass

IC50

Ki

Mod

eof

Inhibition

Test

System

Marke

rRea

ctiona

I maxb

f ub

I/Kic

I u/K

icReferen

ces

Oxy

butynin

Antich

olinergic

4.50

rCYP2C

8Amo

0.03

1,0.01

0.01

,0.01

Walsk

yet

al.,20

05a

Paclitaxe

l(tax

ol)

Antican

cer,

taxa

ne

14.9

30.0

Com

petitive

HLM

Taz

a0.85

0.12

0.03

,0.01

Attar

etal.,20

0313

.3rC

YP2C

8Amo

0.13

0.02

Walsk

yet

al.,20

05a

23–24

rCYP2C

8Amo

0.07

,0.01

O’Don

nellet

al.,20

075.4

Com

petitive

HLM

Amo

0.16

0.02

Van

denB

rink

etal.,20

1189

.8Com

petitive

HLM

Mon

te,0.01

,0.01

Van

denB

rink

etal.,20

116.5

Com

petitive

HLM

Rep

a0.13

0.01

6Van

denB

rink

etal.,20

1112

.0Com

petitive

HLM

Rosi

0.07

,0.01

Van

denB

rink

etal.,20

11Pas

ireotide

Hormon

altherap

y,somas

tatinan

alog

;50

HLM

Pacli

0.01

50.12

,0.01

,0.01

FDA,20

12h

Paz

opan

ibAnticancer,

PKI

10HLM

Pacli

132

,0.01

26.40

0.26

FDA,20

09d

3.72

HLM

Pacli

35.48

0.36

Wan

get

al.,20

14a

PF-562

,271

Anticancer,

PKI

23HLM

n/a

Ron

get

al.,20

08Phen

thoa

tePesticide

10.3

HLM

Amo

Aba

sset

al.,20

09Pioglitaz

one

Antidiabe

tic,

PPAR-g

agon

ist

9.38

1.69

Com

petitive

HLM

Pacli

3.8

,0.01

2.25

0.02

Sah

iet

al.,20

0311

.7rC

YP2C

8Amo

0.65

,0.01

Walsk

yet

al.,20

05a

6.6

Com

petitive

HLM

Amo

0.58

,0.01

Van

denB

rink

etal.,20

117.1

Com

petitive

HLM

Mon

te0.54

,0.01

Van

denB

rink

etal.,20

1137

.6Com

petitive

HLM

Pacli

0.10

,0.01

Van

denB

rink

etal.,20

113.8

Com

petitive

HLM

Rep

a1.00

0.01

Van

denB

rink

etal.,20

116.1

Com

petitive

HLM

Rosi

0.62

,0.01

Van

denB

rink

etal.,20

1114

rCYP2C

8Ceri-1

0.54

,0.01

Floyd

etal.,20

1216

rCYP2C

8Ceri-23

0.48

,0.01

Floyd

etal.,20

12Pitav

astatin(acid,

parent)

Antihyp

erlipide

mic,HMG-

CoA

redu

ctas

einhibitor

57.0

HLM

Pacli

0.02

960.00

5,0.01

,0.01

Sak

aeda

etal.,20

06

Pitav

astatinlacton

eAntihyp

erlipide

mic,HMG-

CoA

redu

ctas

einhibitor

50.5

HLM

Pacli

0.01

900.00

5,0.01

,0.01

Sak

aeda

etal.,20

06

Pon

atinib

Anticanc

er,PKI

6.1

3.05

n/a

n/a

0.16

10.00

080.05

,0.01

FDA,20

12e

Prasu

grel

Antithrombo

tic,

platelet

aggreg

ationinhibitor

.45

.2rC

YP2C

8DBF

1.37

,0.06

1Hag

iharaet

al.,20

08

Prasu

grel

active

metab

olite(R

–13

8727

)Dru

gmetab

olite

.45

.2rC

YP2C

8DBF

Hag

iharaet

al.,20

08

Prasu

grel

thiolacton

e(R

–95

913)

Dru

gmetab

olite

.50

.0rC

YP2C

8DBF

Hag

iharaet

al.,20

08

Prava

statin

(acid,

parent)

Antihyp

erlipide

mic,HMG-

CoA

redu

ctas

einhibitor

.10

0.50

Mixed

HLM

Pacli

0.08

50.57

,0.01

,0.01

Tornioet

al.,20

05

.10

0HLM

Pacli

,0.01

,0.01

Sak

aeda

etal.,20

06Prava

statin

lacton

eAntihyp

erlipide

mic,HMG-

CoA

redu

ctas

einhibitor

99.3

HLM

Pacli

Sak

aeda

etal.,20

06

Profeno

fos

Pesticide

84.0

HLM

Amo

Aba

sset

al.,20

09Prometha

zine

Sed

ative,

antihistam

ine

23HLM

Amo

0.07

0.07

,0.01

,0.01

Nirog

iet

al.,20

14Propo

xyph

ene

Analge

sic,

opioid

32rC

YP2C

8Ceri-1

Floyd

etal.,20

1218

rCYP2C

8Ceri-23

Floyd

etal.,20

12Prothiona

mide

Antitube

rculosis

57.6

HLM

Pacli

Shimok

awaet

al.,20

15Pyrim

etham

ine

Antimalarial

45.1

rCYP2C

8Amo

4.74

0.13

0.21

0.02

7Parikhet

al.,20

07Que

tiap

ine

Antipsych

otic

20HLM

Amo

0.31

40.17

0.03

,0.01

Nirog

iet

al.,20

14Quinidine

Antiarrh

ythmic

98.5

rCYP2C

8Dia

40.13

0.08

0.01

Sai

etal.,20

0013

5.4

rCYP2C

8Phen

a0.06

,0.01

Sai

etal.,20

0050

HLM

Pacli

0.16

0.02

Dierk

set

al.,20

01Quinine

Antim

alarial

11Com

petitive

rCYP2C

8Torse

290.15

2.64

0.40

Ong

etal.,20

00R48

3Antidiab

etic,P

PAR-g

agon

ist

5HLM

Pacli

Web

eret

al.,20

05Rab

eprazole

Antiulcerative,

PPI

12.0

rCYP2C

8Amo

0.9

0.03

70.15

,0.01

Walsk

yet

al.,20

05a

Ran

itidine

Antiulcerative,

H2R

A10

,000

HLM

Pacli

1.31

0.85

,0.01

,0.01

Mon

sarrat

etal.,19

973.1

HLM

Amo

0.85

0.72

Nirog

iet

al.,20

14Reg

orafen

ibAnticanc

er,PKI

1.7

0.6

n/a

n/a

8.1

0.00

513

.50

0.04

FDA,20

12i

(con

tinued

)

202 Backman et al.

TABLE

6—Con

tinued

Inhibitor

Therap

euticUse

and/or

Dru

gClass

IC50

Ki

Mod

eof

Inhibition

Test

System

Marke

rRea

ctiona

I maxb

f ub

I/Kic

I u/K

icReferen

ces

Reg

orafen

ibM2

Dru

gmetab

olite

1.0

n/a

n/a

FDA,20

12i

Reg

orafen

ibM5

Dru

gmetab

olite

1.3

n/a

n/a

FDA,20

12i

Rep

aglinide

Antidiabe

tic,

meg

litinide

analog

27.1

Com

petitive

HLM

Amo

0.10

40.02

6,0.01

,0.01

Van

denB

rink

etal.,20

11

11.1

Com

petitive

HLM

Mon

te,0.01

,0.01

Van

denB

rink

etal.,20

11.10

0Com

petitive

HLM

Pacli

,0.01

,0.01

Van

denB

rink

etal.,20

1123

.0Com

petitive

HLM

Rosi

,0.01

,0.01

Van

denB

rink

etal.,20

11Retinoicacid,all-tran

s(tretino

in)

Antiacne,

retinoid

27.0

Com

petitive

HLM

Pacli

1.15

,0.05

0.04

,0.01

Rah

man

etal.,19

94

Rifam

pin(rifam

picin)

Antibiotic

30.2

Com

petitive

HLM

Pacli

80.40

0.27

0.11

Kajosaa

riet

al.,20

05a

Rifap

entine

Antitube

rculosis

115

HLM

Pacli

34.21

0.02

0.59

0.01

Shimok

awaet

al.,20

15Rilpivirine

Antiviral,NNRTI

13.2–19

.110

.0HLM

Pacli

0.5

,0.01

0.05

,0.01

FDA,20

11d

Riton

avir

Antiviral,pr

otea

seinhibitor

3.03

rCYP2C

8Amo

150.02

9.90

0.20

Walsk

yet

al.,20

05a

1–2

rCYP2C

8Amo

30.00

0.60

O’Don

nellet

al.,20

075.5

HLM

Pacli

5.46

0.11

FDA,20

12j

Rofecox

ibAnti-inflam

matory,

NSAID

95rC

YP2C

8Ceri-1

1.02

0.13

0.02

,0.01

Floyd

etal.,20

1214

rCYP2C

8Ceri-23

0.15

0.02

Floyd

etal.,20

12Rosebe

nga

lXan

then

edy

e53

Hep

Amo

Kaz

miet

al.,20

14

Rosiglitazone

Antidiab

etic,P

PAR-g

agon

ist

18HLM

Pacli

1.7

0.00

20.19

,0.01

Baldw

inet

al.,19

999.58

5.59

Com

petitive

HLM

Pacli

0.30

,0.01

Sah

iet

al.,20

0324

.1–26

.3HLM

Pacli

0.13

,0.01

Kim

etal.,20

05b

10.8

rCYP2C

8Amo

0.13

,0.01

Walsk

yet

al.,20

05a

5.2

Com

petitive

HLM

Amo

0.33

,0.01

Van

denB

rink

etal.,20

114.1

Com

petitive

HLM

Mon

te0.42

,0.01

Van

denB

rink

etal.,20

1128

.6Com

petitive

HLM

Pacli

0.06

,0.01

Van

denB

rink

etal.,20

111.4

Com

petitive

HLM

Rep

a1.21

,0.01

Van

denB

rink

etal.,20

113.0

rCYP2C

8Ceri-1

1.13

,0.01

Floyd

etal.,20

122.7

rCYP2C

8Ceri-23

1.26

,0.01

Floyd

etal.,20

12Rosuva

statin

(acid,

parent)

Antihyp

erlipide

mic,HMG-

CoA

redu

ctas

einhibitor

.10

0.50

Mixed

HLM

Pacli

0.00

460.12

,0.01

,0.01

Tornioet

al.,20

05

.10

0HLM

Pacli

,0.01

,0.01

Sak

aeda

etal.,20

06Rosuv

astatinlacton

eAntihyp

erlipide

mic,HMG-

CoA

redu

ctas

einhibitor

9.8

HLM

Pacli

Fujinoet

al.,20

04

32.5

HLM

Pacli

Sak

aeda

etal.,20

06Salmeterol

Antias

thmatic,b-2-ag

onist

1.87

rCYP2C

8Amo

0.00

40,0.01

Walsk

yet

al.,20

05a

San

guinarine

Antican

cer

10.2

8.9

Non

compe

titive

HLM

Pacli

Qiet

al.,20

13Saq

uina

vir

Antiviral,pr

otea

seinhibitor

1.8

rCYP2C

8Amo

1.41

0.02

1.57

0.03

1Parikhet

al.,20

07Saracatinib

Antican

cer,

PKI

201.8

HLM

Amo

Filpp

ulaet

al.,20

14Sarizotan

Antips

ycho

tic

18.2

dCom

petitive

HLM

Pacli

0.91

0.05

Galleman

net

al.,20

10Satraplatin

(JM-216

)Antican

cer

1–3

0.9

Non

compe

titive

HLM

Pacli

And

oet

al.,19

98Seliciclib(R

-roscovitine

)Anticanc

er,PKI

119

rCYP2C

8DBF

100.10

0.17

0.02

McC

luean

dStuart,

2008

Sertraline

Antide

pressa

nt,SSRI

25.5

rCYP2C

8Amo

0.48

40.02

0.04

,0.01

Walsk

yet

al.,20

05a

350

HLM

Pacli

,0.01

,0.01

FDA,20

08b

.10

0Com

petitive

HLM

Amo

,0.01

,0.01

Van

denB

rink

etal.,20

119.0

Com

petitive

HLM

Mon

te0.05

,0.01

Van

denB

rink

etal.,20

11.10

0Com

petitive

HLM

Pacli

,0.01

,0.01

Van

denB

rink

etal.,20

117.8

Com

petitive

HLM

Rep

a0.06

,0.01

Van

denB

rink

etal.,20

118.1

Com

petitive

HLM

Rosi

0.06

,0.01

Van

denB

rink

etal.,20

1129

.7HLM

Pacli

0.03

,0.01

Erveet

al.,20

1315

HLM

Amo

0.06

,0.01

Nirog

iet

al.,20

14Sim

eprevir(TMC43

5)Antiviral,pr

otea

seinhibitor

(36.8)

HLM

n/a

14.5

,0.00

10.79

,0.01

FDA,20

13h

Sim

vastatin

(lactone

,pa

rent)

Antihyp

erlipide

mic,

HMG-C

oAredu

ctas

einhibitor

9.6

7.1

HLM

Pacli

0.09

60.06

0.01

,0.01

Tornioet

al.,20

05 (con

tinued

)


TABLE

6—Con

tinued

Inhibitor

Therap

euticUse

and/or

Dru

gClass

IC50

Ki

Mod

eof

Inhibition

Test

System

Marke

rRea

ctiona

I maxb

f ub

I/Kic

I u/K

icReferen

ces

5.39

rCYP2C

8Amo

0.04

,0.01

Walsk

yet

al.,20

05a

44.1

HLM

Pacli

,0.01

,0.01

Sak

aeda

etal.,20

068.3

HLM

Amo

0.02

,0.01

Jenk

inset

al.,20

117.5

Com

petitive

HLM

Amo

0.01

,0.01

Van

denB

rink

etal.,20

115.7

Com

petitive

HLM

Mon

te0.02

,0.01

Van

denB

rink

etal.,20

1112

.3Com

petitive

HLM

Pacli

,0.01

,0.01

Van

denB

rink

etal.,20

111.1

Com

petitive

HLM

Rep

a0.09

,0.01

Van

denB

rink

etal.,20

113.3

Com

petitive

HLM

Rosi

0.03

,0.01

Van

denB

rink

etal.,20

113.70

HLM

Pacli

0.05

,0.01

Lee

etal.,20

12a

28rC

YP2C

8Fluo

,0.01

,0.01

Sch

elleman

etal.,20

14Sim

vastatin

acid

Antihyp

erlipide

mic,HMG-

CoA

redu

ctas

einhibitor

66.5

41.1

Mixed

HLM

Pacli

Tornioet

al.,20

05

51.5

HLM

Pacli

Sak

aeda

etal.,20

0676

.5rC

YP2C

8Fluo

Sch

elleman

etal.,20

14Sim

vastatin

acyl-b- D-

gluc

uron

ide

Dru

gmetab

olite

3.8

HLM

Amo

Jenkinset

al.,20

11

SIP

I535

7Antidep

ressan

t,Seroton

in-

norep

inep

hrine-do

pamine

reuptak

einhibitor

89.23

HLM

Pacli

Fan

etal.,20

15

Sitax

entan

Antihyp

ertensive

,ERA

1.58

HLM

Pacli

22.42

28.38

Erveet

al.,20

13Sorafen

ibAnticanc

er,PKI

1-2

rCYP2C

8Amo

21.5

0.01

21.50

0.22

FDA,20

05b

2.4

n/a

n/a

8.96

0.09

Flahe

rtyet

al.,20

111.59

HLM

Pacli

13.52

0.14

Wan

get

al.,20

14a

Spirono

lacton

eDiuretic

6.99

rCYP2C

8Amo

0.44

4,0.10

0.13

0.01

Walsk

yet

al.,20

05a

Stiripe

ntol

Antiepileptic

37.1

35Non

compe

titive

rCYP2C

8Carba

28.17

0.76

Caz

aliet

al.,20

03Sulfap

hen

azole

Antimicrobial

63Com

petitive

rCYP2C

8DTP

Man

cyet

al.,19

960.42

rCYP2C

8R-ibu

-2Ham

man

etal.,19

970.55

rCYP2C

8R-ibu

-3Ham

man

etal.,19

970.36

rCYP2C

8S-ibu

-2Ham

man

etal.,19

970.38

rCYP2C

8S-ibu

-3Ham

man

etal.,19

9750

5rC

YP2C

8Torse

Minerset

al.,20

0017

2.0

rCYP2C

8Dia

Sai

etal.,20

00.50

HLM

Pacli

Dierk

set

al.,20

01Sun

itinib

Anticancer,

PKI

28HLM

Pacli

0.21

0.05

,0.01

,0.01

FDA,20

06b

91.51

HLM

Pacli

,0.01

,0.01

Wan

get

al.,20

14a

Sunitinibmetab

olite

Su01

2662

Dru

gmetab

olite

52HLM

Pacli

FDA,20

06b

Suvo

rexa

nt

Sed

ative,

orex

inreceptor

antago

nist

15HLM

Pacli

0.96

,0.01

0.13

,0.01

FDA,20

14j

Suvo

rexa

ntM9

(L-002

0158

83)

Dru

gmetab

olite

37HLM

Amo

FDA,20

14j

Tam

oxifen

Anticancer,

SERM

3.34

rCYP2C

8Amo

0.32

3,0.02

0.19

,0.01

Walsk

yet

al.,20

05a

3–10

rCYP2C

8Amo

0.22

,0.01

O’Don

nellet

al.,20

073.1

Com

petitive

HLM

Amo

0.10

,0.01

Van

denB

rink

etal.,20

112.1

Com

petitive

HLM

Mon

te0.15

,0.01

Van

denB

rink

etal.,20

1112

.2Com

petitive

HLM

Pacli

0.03

,0.01

Van

denB

rink

etal.,20

1110

.1Com

petitive

HLM

Rep

a0.03

,0.01

Van

denB

rink

etal.,20

112.6

Com

petitive

HLM

Rosi

0.12

,0.01

Van

denB

rink

etal.,20

1114

.3HLM

Pacli

0.06

,0.01

Lee

etal.,20

12a

2.3

HLM

Amo

0.28

,0.01

Nirog

iet

al.,20

14Tan

espimycin

Anticanc

er29

HLM

Pacli

17.34

,0.10

1.20

0.12

Gan

etal.,20

12Tas

imelteon

Circadian

regu

lator

.10

0HLM

Amo

0.80

;0.10

0.02

,0.01

FDA,20

14m

Tas

imelteon

M12

Dru

gmetab

olite

.10

0HLM

Amo

FDA,20

14m

Teg

aserod

Gas

trop

rokine

tic,

5-HT4

receptor

agon

ist

;13

0HLM

Pacli

0.00

650.02

,0.01

,0.01

Vicke

rset

al.,20

01 (con

tinued

)

204 Backman et al.

TABLE

6—Con

tinued

Inhibitor

Therap

euticUse

and/or

Dru

gClass

IC50

Ki

Mod

eof

Inhibition

Test

System

Marke

rRea

ctiona

I maxb

f ub

I/Kic

I u/K

icReferen

ces

Telithr

omycin

Antibiotic

87rC

YP2C

8Pacli

2.7

0.30

0.06

0.02

Yoshida

etal.,20

12Tem

sirolimus

Anticancer,

PKI

27HLM

Pacli

0.57

0.02

FDA,20

07d

Terbinafine

Antifunga

l;15

0HLM

Pacli

3,0.01

Vicke

rset

al.,19

99Terfena

dine

Antihistamine

5Non

compe

titive

rCYP2C

8Torse

0.00

330.03

,0.01

,0.01

Onget

al.,20

0011

.5rC

YP2C

8Amo

,0.01

,0.01

Walsk

yet

al.,20

05a

19.1

HLM

Pacli

,0.01

,0.01

Erveet

al.,20

13Terifluno

mide

Immun

osupp

ressan

t,dr

ug

metab

olite

0.17

4–0.21

90.10

0-0.15

0Com

petitive

,mixed

HLM

Pacli

0.11

0.05

1.1

0.06

FDA,20

12l

Ticag

relor

Antithrombo

tic,

platelet

aggreg

ationinhibitor

.50

HLM

Pacli

1.3

,0.02

Zhou

etal.,20

11;FDA,

2011

bTicag

relormetab

oliteAR-

C12

4910

XX

Dru

gmetab

olite

43HLM

Pacli

FDA,20

11b

Ticlopidine

Antithrombo

tic,

platelet

aggreg

ationinhibitor

100

rCYP2C

82-TPE

30.02

0.06

,0.01

Ha-Duo

nget

al.,20

01

43.9

rCYP2C

8DBF

0.14

,0.01

Hag

iharaet

al.,20

0829

HLM

Amo

0.21

,0.01

Nirog

iet

al.,20

15Tipranav

irAntiviral,pr

otea

seinhibitor

2.1

rCYP2C

8Amo

94.8

,0.01

90.29

,0.90

Parikhet

al.,20

07Tolbu

tamide

Antidiabe

tic,

sulfon

ylur

ea2,37

0Mixed

HLM

Pacli

196

0.09

0.08

,0.01

Rah

man

etal.,19

94Trametinib

Anticanc

er,PKI

0.34

HLM

Rosi

0.03

20.03

80.19

0.01

FDA,20

13f

Tranylcypr

omine

Antide

pressa

nt,MAOI

26–35

HLM

Pacli

0.42

0.03

Dierk

set

al.,20

0112

.1rC

YP2C

8Amo

0.07

Walsk

yet

al.,20

05a

103–

113

rCYP2C

8Amo

,0.01

O’Don

nellet

al.,20

0711

.24

rCYP2C

8Pacli

0.07

Gao

etal.,20

1022

.5HLM

Amo

0.04

Nirog

iet

al.,20

15Triam

cinolon

eAnti-inflammatory,

glucocorticoid

19.3

rCYP2C

8Amo

Walsk

yet

al.,20

05a

32.5

Com

petitive

HLM

Amo

Van

denB

rink

etal.,20

1153

.1Com

petitive

HLM

Mon

teVan

denB

rink

etal.,20

11.10

0Com

petitive

HLM

Pacli

Van

denB

rink

etal.,20

1142

.5Com

petitive

HLM

Rep

aVan

denB

rink

etal.,20

1120

.4Com

petitive

HLM

Rosi

Van

denB

rink

etal.,20

11Triaz

olam

Sed

ative,

benz

odiazepine

25Non

compe

titive

rCYP2C

8Torse

0.01

30.09

9,0.01

,0.01

Onget

al.,20

00Trimethop

rim

Antim

icrobial,dihyd

rofolate

redu

ctas

einhibitor

75rC

YP2C

8Pacli

40.63

0.05

0.03

Wen

etal.,20

02

5432

Com

petitive

HLM

Pacli

0.13

0.08

Wen

etal.,20

0251

.529

.0Com

petitive

HLM

Rosi-OH

0.14

0.09

Hru

skaet

al.,20

0571

HLM

Pio

0.11

0.07

Jaak

kola

etal.,20

06c

40.6

rCYP2C

8Amo

0.20

0.12

Parikhet

al.,20

0734

.1Com

petitive

rCYP2C

8Pio

0.12

0.07

Tornioet

al.,20

08b

38.2

Com

petitive

HLM

Pio

0.10

0.07

Tornioet

al.,20

08b

9.2

Com

petitive

HLM

Amo

0.43

0.27

Van

denB

rink

etal.,20

11.10

0Com

petitive

HLM

Mon

te,0.04

,0.03

Van

denB

rink

etal.,20

11.10

0Com

petitive

HLM

Pacli

,0.04

,0.03

Van

denB

rink

etal.,20

118.5

Com

petitive

HLM

Rep

a0.47

0.30

Van

denB

rink

etal.,20

1113

.2Com

petitive

HLM

Rosi

0.30

0.19

Van

denB

rink

etal.,20

114.5–

17HLM

Amo

1.78

1.12

Dinge

ret

al.,20

1412

2Hep

Amo

0.07

0.04

Kosugi

etal.,20

1417

.41–

20.38

HLM

Pacli

0.46

0.29

Pen

get

al.,20

15Troglitaz

one

Antidiabe

tic,

PPAR-g

agon

ist

1–5

0.3

Com

petitive

rCYP2C

8Pacli

3,0.01

10.00

,0.10

Yam

azak

iet

al.,20

0015

–20

HLM

Pacli

0.30

,0.01

Yam

azak

iet

al.,20

002.33

2.59

Com

petitive

HLM

Pacli

1.16

0.01

Sah

iet

al.,20

039.78

rCYP2C

8Pacli

0.61

,0.01

Gao

etal.,20

10Troglitaz

oneM1

Dru

gmetab

olite

9–41

rCYP2C

8Pacli

Yam

azak

iet

al.,20

00Troglitaz

oneM3

Dru

gmetab

olite

6-26

3.0

Com

petitive

rCYP2C

8Pacli

Yam

azak

iet

al.,20

0039

–.50

HLM

Pacli

Yam

azak

iet

al.,20

00

(con

tinued

)


TABLE

6—Con

tinued

Inhibitor

Therap

euticUse

and/or

Dru

gClass

IC50

Ki

Mod

eof

Inhibition

Test

System

Marke

rRea

ctiona

I maxb

f ub

I/Kic

I u/K

icReferen

ces

Trolean

domycin

Antibiotic

953.0

rCYP2C

8Phe

na3

,0.01

Sai

etal.,20

00TSAHC

Antican

cer

1.0

0.81

Non

compe

titive

HLM

Amo

Imet

al.,20

12Ulipr

istal

Con

tracep

tive

,pr

ogesterone

receptor

mod

ulator

2.6

HLM

Pacli

0.03

7,0.06

0.03

,0.01

FDA,20

10b

UTL-5g

Chem

oprotective,

TNF-a

inhibitor

61.2

HLM

Rosi-OH

Wuet

al.,20

14

Valde

coxib

Anti-inflammatory,

NSAID

15.0

rCYP2C

8Amo

0.51

20.02

0.07

,0.01

Walsk

yet

al.,20

05a

Vem

urafenib

Anticancer,

PKI

12HLM

n/a

125

,0.01

20.9

0.21

EMA,20

12d

Vidupipr

ant(A

MG

853)

Antias

thmatic,PGD2

receptor

antago

nist

1.8

Bipha

sic

HLM

Mon

teFotiet

al.,20

12

5.4

1.1

Com

petitive

HLM

Pacli

Fotiet

al.,20

126.0

Com

petitive

HLM

Rosi

Fotiet

al.,20

12Vidupipr

antacyl

glucu

ronide(M

1)Dru

gmetab

olite

7.3

Bipha

sic

HLM

Mon

teFotiet

al.,20

12

2.7

Mixed

HLM

Pacli

Fotiet

al.,20

126.9

Mixed

HLM

Rosi

Fotiet

al.,20

12Vilaz

odon

eAntide

pressa

nt,SSRI

1.8

0.46

Com

petitive

HLM

Pacli

0.33

0.04

0.72

0.03

FDA,20

11g

Vinblas

tine

Anticancer

100

HLM

Pacli

Mon

sarrat

etal.,19

97Vincristine

Antican

cer

8HLM

Pacli

0.43

0.11

Mon

sarrat

etal.,19

97Vismod

egib

(GDC-044

9)Anticanc

er,SMO

Antago

nist

6.0

Non

compe

titive

HLM

Pacli

16.4

0.01

2.73

0.03

Won

get

al.,20

09;

LoR

usso

etal.,20

13Vorap

axar

Antithrombo

tic,

platelet

aggreg

ationinhibitor

1.5

0.86

Mixed

HLM

n/a

0.05

270.00

20.06

,0.01

Chen

etal.,20

14,FDA,

2014

lVortiox

etine

Antide

pressa

nt,SMS

9.34

HLM

n/a

0.04

724

0.02

,0.01

,0.01

FDA,20

13j

Vortiox

etinemetab

oliteLu

AA34

443

Dru

gmetab

olite

4.24

HLM

n/a

FDA,20

13j

Zafirluka

stAntiasthm

atic,LTRA

0.64

4rC

YP2C

8Amo

0.29

5,0.01

0.92

,0.01

Walsk

yet

al.,20

05a

0.38

8HLM

Amo

1.52

0.02

Walsk

yet

al.,20

05a

0.78

HLM

Pio

0.76

Jaak

kola

etal.,20

06c

.10

0Hep

Amo

,0.01

,0.01

Kosugi

etal.,20

140.01

4HLM

Amo

42.14

0.42

Nirog

iet

al.,20

14

3-ASBA,3-(anilinosulfon

yl)-be

nzenecarbo

xylic

acid;5-HT,5-hyd

roxy

tryp

tamine

(seroton

in);

5-MeO

-DIP

T,5-methox

y-N,N

-diisopr

opyltryp

tamine;

ARB,an

gioten

sin

IIreceptor

blocke

r;BTFM

gemfibrozil,5-(2,5-bis

(trifluo

romethyl)phen

oxy)-2,2-dim

ethylpe

ntanoicacid;C

CB,calcium

chan

nel

blocke

r;CP-778

875;

5-(N

-(4-((4-ethy

lben

zyl)thio)phe

nyl)su

lfam

oyl)-2-m

ethy

lben

zoic

acid;E

RA,e

ndothe

linreceptor

antago

nist;f

u,fractionun

boundin

plas

ma;

GABA,g

-aminob

utyricacid;H

2RA,H

-2receptor

antago

nist;HLM,h

uman

live

rmicrosomes;H

MG-C

oA,3

-hyd

roxy

-3-m

ethylglutaryl-coen

zymeA;I

C50,inhibitor

concentrationsu

pportinghalfof

themax

imal

inhibition;

I max,

peak

inhibitor

conc

entration

inplas

ma;

Ki,reve

rsible

inhibition

constan

t;LABA,long-actingb-adr

enocep

torag

onist;

LTRA,leuko

trienereceptor

antago

nist;

MAO,mon

oamineox

idas

e;MMB4DMS,1,19-m

ethylen

ebis

[4-[(hyd

roxy

imino)methy

l]-pyridinium]dimethan

esulfon

ate;

c-mpl,mye

lopr

oliferativeleuk

emia;n/a,

notav

ailable;

NNRTI,

nonn

ucleosidereve

rsetran

scriptas

einhibitor;NS,non

stru

cturalpr

otein;NSAID

,non

steroida

lan

ti-

inflam

matorydr

ug;

PDE,ph

osph

odiesteras

e;PGD2,

prostaglan

din

D2;

PKI,

protein

kinas

einhibitor;PPAR,pe

roxisomepr

oliferator-activated

receptor;PPI,

proton

pumpinhibitor;rC

YP2C

8,recombinan

tCYP2C

8;SERM,

selectiveestrog

enreceptor

mod

ulator;SGLT,sod

ium-glucose

linke

dtran

sporter;SMO,smoo

then

edreceptor;S

MS,seroton

inmod

ulatoran

dstim

ulator;SNRI,serotonin-norep

inep

hrinereup

take

inhibitor;S

SRI,selectiveserotonin

reuptak

einhibitor;TNF,tumor

necrosisfactor;TSAHC,4

-(p-toluen

esulfon

ylam

ido)-4-hyd

roxy

chalcone;

XO,x

anthineox

idas

e;UTL-5g,

N-(2,4-dich

loroph

enyl)-5-methy

l-1,2-ox

azole-3-carbox

amide.

a2-TPE,2-aroy

lthioph

en5-hyd

yrox

ylation;Ami,am

inop

yrineN-dem

ethylation;Amo,

amod

iaqu

ineN-dee

thylation;Carba

,carbam

azep

ine10

,11-ep

oxidation;Ceri-1,

ceriva

statin

demethylation

(M-1);

Ceri-23

,ceriva

statin

6-hyd

roxy

lation

(M-23);D

BF,d

iben

zylfluorescein

(fluorescentreaction

);Dia,diaz

epam

N-dem

ethylation;D

TP,2

,3-dichloro-4(2-then

oyl)ph

enol

5-hyd

roxy

lation

;Fluo,

fluorom

etricreaction

;R-ibu

-2,R

-ibu

profen

2-hyd

roxy

lation

;R-ibu

-3,R

-ibu

profen

3-hyd

roxy

lation

;S-ibu

-2,S

-ibu

profen

2-hyd

roxy

lation

;S-ibu

-3,S

-ibu

profen

3-hyd

roxy

lation

;Luci,luciferin-6

methyl

ether

demethylation(luminog

enicreaction

);Mon

te,m

onteluka

st36

-hyd

roxy

lation

;Mon

te-4,

form

ationof

mon

teluka

stmetab

olite4;

Pacli,p

aclitaxe

l6a-hyd

roxy

lation

;Phen

a,ph

enan

threnehyd

roxy

lation

;Pio,p

ioglitaz

onehyd

roxy

lation

(M-IV);Rep

a,repa

glinide39-hyd

roxy

lation

;Rosi,rosiglitaz

oneN-dem

ethylation;R

osi-

OH,rosiglitaz

onep-hyd

roxy

lation

;Taz

a,taza

rotenic

acid

sulfox

idation;

Tolbu

,tolbutamidemethy

lhyd

roxy

lation

;Torse,torsemidemethylhyd

roxy

lation

.bThis

inform

ationis

prim

arilyba

sedon

inform

ationfrom

theUW

Metab

olism

andTransp

ortDru

gIn

teractionDatab

ase(D

IDB),Cop

yrightUniversity

ofWas

hington

1999

-201

5(D

IDB

accessed

May

-Sep

tembe

r,20

15),an

dseconda

rily

oninform

ationfrom

Martinda

le:TheCom

pleteDru

gReferen

ce.Lon

don:Pharmaceu

ticalPress

(electronic

version),Tru

venHea

lth

Analytics(H

ealthcare),Green

woo

dVillage

,Colorad

o.Ava

ilab

leat:http://w

ww.

micromed

exsolution

s.com/(Martinda

leaccessed

June-Sep

tembe

r,20

15).In

case

seve

ralva

lues

wererepo

rted

forI m

axan

df u,thehighestva

lues

wereselected

.c W

hen

expe

rimen

tallyde

term

ined

Kiwas

not

available,

Kiwas

calculatedas

IC50/2.A

nI/Ki.

1.0indicatesthat

aclinically

releva

ntinhibitionis

like

ly,I/K

i=0.1–

1indicatesthat

aclinically

releva

ntinhibition

ispo

ssible,I/K

i,

0.1indicatesthat

aclinically

releva

ntinhibitionis

unlike

ly.

dUnbo

undva

lue.

206 Backman et al.

http://www.micromedexsolutions.com/

http://www.micromedexsolutions.com/

TABLE 7Natural and endogenous compounds that act as reversible CYP2C8 inhibitors

Inhibitor Description IC50 KiMode ofInhibition

TestSystem

MarkerReactiona References

mM (mg/ml) mM (mg/ml)

3-Isomangostin Constituent ofmangosteen

0.64 0.66 Competitive HLM Pacli Foti et al., 2009

6-Gingerol Constituent of gingerroot

(6.5) HLM Amo Mukkavilli et al., 2014

6-Prenylnaringenin Prenylflavonoid 1.9 HLM Amo Yuan et al., 20146-Shogaol Constitutent of ginger

root(0.8) HLM Amo Mukkavilli et al., 2014

8-Desoxygartanin Constituent ofmangosteen

1.85 2.80 Competitive HLM Pacli Foti et al., 2009



8-Prenylnaringenin(flavaprenin)

Prenylflavonoid 0.6 HLM Amo Yuan et al., 2014

9-Hydroxycalabaxanthone Constituent ofmangosteen

14.1 HLM Pacli Foti et al., 2009



11-Keto-b-boswellic acid Triterpene 9.5 HLM Pacli Frank and Unger, 2006Acetyl-a-boswellic acid Triterpene 65.8 HLM Pacli Frank and Unger, 2006Acetyl-b-boswellic acid Triterpene 33.4 HLM Pacli Frank and Unger, 2006Acetyl-11-keto-b-boswellic

acidTriterpene 10.1 HLM Pacli Frank and Unger, 2006

Allocryptopine Alkaloid 10-100 rCYP2C8 DBF Salminen et al., 2011Arachidonic acid Endogenous

compound7 Competitive rCYP2C8 Pacli Yamazaki and Shimada,

1999b-Boswellic acid Triterpene 8.7 HLM Pacli Frank and Unger, 2006Bo-yang-hwan-o-tang Oriental herbal

medicine(17,209) HLM Pacli Lee et al., 2012b

BST204 Dry extract of ginseng (17.4) HLM Rosi Zheng et al., 2014Capnoidine Alkaloid 10-100 rCYP2C8 DBF Salminen et al., 2011Cedrol Sesquiterpene 41.0 HLM Amo Jeong et al., 2014Corybulbine Alkaloid 10-100 rCYP2C8 DBF Salminen et al., 2011Corycavamine Alkaloid 10-100 rCYP2C8 DBF Salminen et al., 2011Corycavidine Alkaloid 10-100 rCYP2C8 DBF Salminen et al., 2011Corydaline Alkaloid 10-100 rCYP2C8 DBF Salminen et al., 2011Corypalmine Alkaloid 10-100 rCYP2C8 DBF Salminen et al., 2011Cranberry (powder) Natural product (24.7) HLM Amo Albassam et al., 2015

(24.0) HLM Pio Albassam et al., 2015Cryptopine Alkaloid 10-100 rCYP2C8 DBF Salminen et al., 2011b-Cryptoxanthin Carotenoid pigment 13.8 HLM Pacli Zheng et al., 2013Cudratricusxanthone Constituent of

Cudraniatricuspidata

4.69 2.2 Noncompetitive HLM Pacli Sim et al., 2015

Curcumin Diarylheptanoid 129.7 rCYP2C8 DBF Mach et al., 2010DA-9801 Extract (449.9) HLM Amo Ji et al., 2013Dioscorea nipponica Extract (237.1) HLM Amo Ji et al., 2013Diosmetin Flavonoid 3.13 Mixed HLM Pacli Quintieri et al., 2011Ellagic acid Constitutent of guava

leaf(13.99) rCYP2C8 DBF Kaneko et al., 2013

(2)-Epigallocatechin-3-gallate

Catechin 10.9 6.8 Competitive HLM Amo Misaka et al., 2013

Eupatilin Flavone 104.9 101.9 Competitive HLM Amo Ji et al., 2010Feverfew herb Natural product (104–126) rCYP2C8 Pacli Unger and Frank, 2004Fisetin Flavonol 10.8 1.3–6.0 Mixed HLM Pacli Václavíková et al., 2003Gartanin Constituent of

mangosteen6.28 HLM Pacli Foti et al., 2009

Ginger extract Extract (122.5) HLM Amo Mukkavilli et al., 2014Green tea extract Extract (4.5) HLM Amo Misaka et al., 2013Guava leaf extract Extract (18.16) rCYP2C8 DBF Kaneko et al., 2013Guava leaf polyphenol Constitutent of guava

leaf(1.45) rCYP2C8 DBF Kaneko et al., 2013

Gypenosides Oriental herbalmedicine

(20.06) HLM Pacli He et al., 2013

Hesperedin Flavonoid 274.7 rCYP2C8 Tolbu Pang et al., 2012Hesperetin Flavonoid 68.5 HLM Pacli Quintieri et al., 2011

168.4 rCYP2C8 Tolbu Pang et al., 2012Hibiscus sabdariffa

extractExtract (424) HLM Amo Johnson et al., 2013

Honey Natural product (102.9) (50.5) Competitive rCYP2C8 Amo Muthiah et al., 2012Honokiol Constituent of

Magnolia8.9 4.9 Competitive HLM Amo Jeong et al., 2013

Horsetail Natural product (93.0) HLM Amo Sevior et al., 2010

(continued )


TABLE 7—Continued


TestSystem


Hops extract Extract 0.8 HLM Amo Yuan et al., 2014Hunnemannine Alkaloid 1–10 rCYP2C8 DBF Salminen et al., 2011Hyperforin Constituent of

St. John’s Wort56 HLM Amo Hokkanen et al., 2011

Hypoxis hemerocallideaextract

Extract (192) HLM Pacli Fasinu et al., 2013a

Isocorybulbine Alkaloid 10–100 rCYP2C8 DBF Salminen et al., 2011Isoxanthohumol Prenylflavonoid 0.2 HLM Amo Yuan et al., 2014Jaceosidin Flavone 106.4 109.4 Competitive HLM Amo Ji et al., 2010Labisia pumila extracts Extracts (2.39–352.3) (0.70-33.9) Noncompetitive,

mixedrCYP2C8 DBF Pan et al., 2012

b-Lapachone Quinone 3.8 HLM Pacli Kim et al., 2013aLiquorice extract Extract (14.36–17.06) HLM Amo Li et al., 2015Liquorice root Natural product (22.6) HLM Amo Sevior et al., 2010Luteolin Flavonoid 82.0 rCYP2C8 Tolbu Pang et al., 2012a-Mangostin Constituent of

mangosteen0.88 0.64 Competitive HLM Pacli Foti et al., 2009

b-Mangostin Constituent ofmangosteen

8.39 HLM Pacli Foti et al., 2009

Mecambridine Alkaloid 10–100 rCYP2C8 DBF Salminen et al., 2011Milk thistle extract Extract (8.35) Mixed HLM Pacli Doehmer et al., 2011Morin Flavonol 17.3 7.3-12.3 Mixed HLM Pacli Václavíková et al., 2003Nantenine Alkaloid 1–10 rCYP2C8 DBF Salminen et al., 2011a-Naphthoflavone Flavone derivative 0.36 HLM Amo Nirogi et al., 2015Obovatol Constituent of

Magnolia11.1 HLM Amo Joo et al., 2013

Quercetin Flavonoid 1.29 Competitive rCYP2C8 Pacli Rahman et al., 19941.14 Competitive HLM Pacli Rahman et al., 1994

7 HLM Pacli Dierks et al., 20011.96-2.35 Competitive rCYP2C8 Amo Li et al., 2002

1.56 Competitive HLM Amo Li et al., 20022.47 rCYP2C8 DBF Yamamoto et al., 20024.07 19.7 HLM Taza Attar et al., 2003

10.1 Competitive HLM Pacli Bun et al., 200320.6 HLM DBF Ghosal et al., 20033.3 HLM Pacli Cai et al., 20046.3 HLM Pacli Donato et al., 20042.9 THLE DBF Donato et al., 200429.5 THLE Pacli Donato et al., 2004

3.9–6.2 rCYP2C8 Pacli Unger and Frank, 20043.33 rCYP2C8 Amo Walsky and Obach,

20043.06 HLM Amo Walsky and Obach,

20047.19–8.47 HLM Pacli Kim et al., 2005b

57.8 HLM Amo Turpeinen et al., 20053.94 rCYP2C8 Amo Walsky et al., 2005a

3.3–5.6 rCYP2C8 Amo O’Donnell et al., 20071.6 rCYP2C8 DBF McClue and Stuart,

20085.28–5.38 rCYP2C8 Pacli Gao et al., 2010

1.33 rCYP2C8 Bomcc Liu et al., 2010a0.029 HLM Amo Teng et al., 20100.49 Competitive HLM Amo VandenBrink et al.,

20110.52 Competitive HLM Monte VandenBrink et al.,

20113.0 Competitive HLM Pacli VandenBrink et al.,

20110.61 Competitive HLM Repa VandenBrink et al.,

20110.61 Competitive HLM Rosi VandenBrink et al.,

20114.20 2.07 Competitive rCYP2C8 Amo Muthiah et al., 20121.39 HLM Pacli Lee et al., 2012a46.0 rCYP2C8 Tolbu Pang et al., 201218.7 HLM Pacli Bymaster et al., 2013(0.59) rCYP2C8 DBF Kaneko et al., 2013

(0.3702) HLM Amo Mukkavilli et al., 201424.5 rcCYP2C8 DBF Pan et al., 201412.3 HLM Rosi-OH Wu et al., 2014

3.40–5.92 HLM Amo Li et al., 20151.2 HLM Amo Nirogi et al., 2015

Piperlonguminine Alkaloid 76.2 HLM Amo Song et al., 2014b

(continued )

208 Backman et al.

and organic anion transporter (OAT) 3 (Ki = 6.8 mM)(Schneck et al., 2004; Shitara et al., 2004; Nakagomi-Hagihara et al., 2007). The strong interactions betweengemfibrozil and CYP2C8 substrate drugs observed invivo are mainly due to its glucuronide metabolite(Ogilvie et al., 2006). Gemfibrozil 1-O-b glucuronideaffects CYP2C8 by mechanism-based inhibition (sec-tions V.B and VI.B).In vitro, the thiazolidinedione drugs pioglitazone,

rosiglitazone, and troglitazone are potent, competitiveinhibitors of CYP2C8with IC50 andKi values of,40mM(Table 6). However, e.g., pioglitazone does not affectCYP2C8 in vivo, likely because of its extensive proteinbinding (Kajosaari et al., 2006a).The antiviral agents atazanavir and efavirenz inhibit

CYP2C8 in vitro with Ki values of 2.1 and 4.8 mM,respectively [inhibitor concentration (I) to Ki ratios(I/Ki) = 3.7 and 6.3, respectively] (Table 6). In vivo,atazanavir has slightly affected the pharmacokineticsof rosiglitazone (FDA, 2015b). According to predictions,efavirenz may increase the area under the plasmaconcentration-time curve (AUC) of CYP2C8 substratesby more than fourfold at steady state, and such effectshave been observed in vivo (German et al., 2007).The immunosuppressant teriflunomide inhibits

CYP2C8 with a very low Ki of 0.10–0.15 mM (FDA,2012a). Thus, its estimated I/Ki ratio of 1.1 indicatesthat interactions between teriflunomide and CYP2C8substrate drugs are likely, in agreement with in vivofindings (section IV.C.2).Numerous protein kinase inhibitors inhibit CYP2C8

to various degrees in vitro (Table 6). However, for themost part, their in vivo inhibitory effects on CYP2C8have not been studied. For those whose inhibition hasbeen examined in a clinical setting, it seems to be rather

small/moderate. For instance, axitinib inhibits CYP2C8in vitro with aKi of 0.2–0.5 mM (I/Ki = 0.3–0.9), but it didnot alter paclitaxel plasma concentrations in patients(FDA, 2012f; Wang et al., 2014a). Similarly, cabozanti-nib is a noncompetitive inhibitor of CYP2C8 in vitro(Ki = 4.6 mM, I/Ki = 0.7), but the in vivo pharmacokineticsof rosiglitazone was not affected by cabozantinib (FDA,2012c; Nguyen et al., 2015). The inhibition of CYP2C8by pazopanib (Ki of 3.7 mM, I/Ki = 35) may be of clinicalrelevance (FDA, 2009d; Tan et al., 2014; Wang et al.,2014b). Nilotinib is a strong competitive CYP2C8 in-hibitor in vitro (Ki = 0.1–0.9 mM, I/Ki = 4.8–43), but italso induces CYP2C8 (FDA, 2007c). Hence, a clinicalinteraction study with a CYP2C8 probe substrate hasbeen recommended by the FDA to evaluate the in vivoeffect on CYP2C8 activity by nilotinib. Similarly, aninteraction study with a CYP2C8 substrate drug hasalso been recommended for regorafenib, which inhibitsCYP2C8 with a Ki value of 0.6 mM in vitro (I/Ki = 13.5)(FDA, 2012i). In addition, sorafenib seems to be a strongCYP2C8 inhibitor in vitro with Ki values, 3 mM (I/Ki =9–22) (Table 6), but the effect of sorafenib on CYP2C8in vivo has not been evaluated.

Also several other anticancer agents exhibit inhibi-tion of CYP2C8 in vitro (Table 6). For instance, theandrogen receptor antagonist enzalutamide is both asubstrate and inhibitor of CYP2C8 in vitro (Ki = 5.5 mM,I/Ki = 6.5) (FDA, 2012k). Vismodegib, an oral hedgehogpathway inhibitor, inhibits CYP2C8 in vitro with aKi of6.0 mM (I/Ki = 2.7), but vismodegib at steady state didnot affect the pharmacokinetics of rosiglitazone (Wonget al., 2009; LoRusso et al., 2013).

The iron chelator deferasirox inhibits CYP2C8 withan IC50 of 100 mM (I/Ki ,0.01) (FDA, 2005a), but it hasincreased repaglinide AUC by 2.3-fold in vivo (Skerjanec

TABLE 7—Continued


TestSystem


Reserveratrol Stilbenoid 26.5 16.2–20.7 HLM Pacli Václavíková et al., 2003Saw palmetto Natural product (8) HLM Amo Sevior et al., 2010

(15.4) HLM Amo Albassam et al., 2015(9.6) HLM Pio Albassam et al., 2015

Scoulerine Alkaloid 10-100 rCYP2C8 DBF Salminen et al., 2011Star fruit (averrhoa

carambola) juiceFruit juice 2.2b HLM Pacli Zhang et al., 2007b

Sutherlandia frutescens Herb (22.4) HLM Pacli Fasinu et al., 2013bTanshinol borneol ester Combination of the

natural compoundsdanshensu andborneol

105 rCYP2C8 Bomcc Liu et al., 2010b

Thalictricavine Alkaloid 10–100 rCYP2C8 DBF Salminen et al., 2011Thelephoric acid Antioxidant 24.6 HLM Amo Song et al., 2014aTiliroside Flavonoid 12.1 9.4 Competitive HLM Pacli Sun et al., 2010Tualang honey Natural product (102.9) (50.5) Competitive rCYP2C8 Amo Muthiah et al., 2012Valerian Natural product (523.3) HLM Amo Sevior et al., 2010Xanthohumol Natural product 1.1 HLM Amo Yuan et al., 2014

HLM, human liver microsomes; IC50, inhibitor concentration supporting half of the maximal inhibition; Ki, reversible inhibition constant; n/a, not available; rcCYP2C8,reconstituted CYP2C8; rCYP2C8, recombinant CYP2C8; THLE, immortalized human liver epithelial cells.

aAmo, amodiaquine N-deethylation; Bomcc, flurogenic substrate; DBF, dibenzylfluorescein; Monte, montelukast 36-hydroxylation; Pacli, paclitaxel 6a-hydroxylation; Pio,pioglitazone hydroxylation (M-IV); Repa, repaglinide 39-hydroxylation; Rosi, rosiglitazone N-demethylation; Rosi-OH, rosiglitazone p-hydroxylation; Taza, tazarotenic acidsulfoxidation; Tolbu, tolbutamide methyl hydroxylation.

b% (v/v).


et al., 2010). Febuxostat, a xanthine oxidase inhibitor,inhibits CYP2C8 in vitro with a Ki of 20 mM, suggestingthat the inhibition may be of clinical relevance (I/Ki =0.8). However, febuxostat at steady state had no effecton the concentrations of a single dose of rosiglitazone invivo (Naik et al., 2012). Similarly, rosiglitazone phar-macokineticswas not affected by the platelet aggregationinhibitor vorapaxar in vivo (Ki = 0.86 mM, I/Ki = 0.06)(Chen et al., 2014; FDA, 2014l).Sulfaphenazole, ketoconazole, diethyldithiocarba-

mate, methoxsalen (8-methoxypsoralen), and tranylcy-promine, commonly used as in vitro inhibitors ofCYP2C9, CYP3A4, CYP2E1, CYP2A6, and CYP2C19,respectively, also inhibit CYP2C8 in vitro (Table 6). Forinstance, sulfaphenazole is a strong competitive in-hibitor of CYP2C9 with a Ki of 0.3 mM, whereas its Ki

for CYP2C8 inhibition is 0.4–63 mM (Mancy et al., 1996;Hamman et al., 1997).2. Natural Compounds. A range of natural com-

pounds have been tested for CYP2C8 inhibition in vitro,and inhibition parameters have been determined forseveral of them (Table 7). In a CYP inhibition screeningof 10 herbal products commercially available in Aus-tralia, horsetail (Equisetum arvense) affected CYP2C8with an IC50 of 93.0 mg/ml (Sevior et al., 2010). Theauthors suggested that the inhibition of CYP2C8 byhorsetail, which is used for treatment of urinary tractinfections, cystitis, and prostate problems, may beclinically relevant (Sevior et al., 2010). In another invitro study, six herbal supplements inhibited CYP2C8to various degree, but the inhibition by cranberrypowder (IC50 = 24.7 mg/ml) and saw palmetto (IC50 =15.4 mg/ml) were suggested to potentially be of clinicalsignificance (Albassam et al., 2015).Among five CYP enzymes tested, CYP2C8 was most

sensitive to inhibition by green tea extract in HLM(IC50 = 4.5mg/ml) (Misaka et al., 2013). Themajor catechinin green tea, (2)-epigallocatechin-3-gallate, inhibitedCYP2C8 with a Ki of 6.8 mM, indicating that green teaintake may affect CYP2C8 in vivo. It has been reportedthat 15% of Japanese older than 40 years of ageconsume more than 1.8 l of green tea daily, correspond-ing to a daily epigallocatechin-3-gallate intake of 540–720 mg (Misaka et al., 2013).

B. Metabolism-dependent Inhibition

Metabolism-dependent inhibitors are compoundsthat are metabolized to metabolites or reactive inter-mediates that cause time-dependent enzyme inhibition.Metabolism-dependent inhibition may be either direct,quasi-irreversible, or irreversible (mechanism-basedinhibition). Mechanism-based inhibitors inactivatetheir victim enzymes permanently, and enzyme activitycan only be regained by de novo synthesis of theenzyme (Lin and Lu, 1998). Interestingly, two glucuro-nide metabolites, gemfibrozil 1-O-b glucuronide andclopidogrel acyl 1-b-D-glucuronide, affect CYP2C8 by

mechanism-based inhibition or quasi-irreversible in-hibition, leading to clinically important drug-druginteractions (Figs. 2 and 5; Table 8; Ogilvie et al.,2006; Tornio et al., 2014). Very recently, also the acylglucuronide of deleobuvir, an HCV protease inhibitor,was found to be a very potent mechanism-based in-hibitor of CYP2C8 (Sane et al. 2015). In addition, thereis in vitro evidence suggesting that the carbamoylglucuronide metabolite of Lu AA34893 may affectCYP2C8 in a similar manner (Kazmi et al., 2010). Ofinterest, parent clopidogrel and gemfibrozil do not seemto be metabolized by CYP2C8. For example, clopidogrelis mainly eliminated by carboxylesterase 1, whereas itsactivation is dependent on CYP2C19 and CYP3A4(Mega et al., 2009; Simon et al., 2009; Holmberg et al.,2014; Tarkiainen et al., 2015).

The inhibitory effect of gemfibrozil on CYP2C8 isbased principally on its metabolite, gemfibrozil 1-O-bglucuronide, which is formed mainly by UGT2B7 inhepatocytes (Shitara et al., 2004; Ogilvie et al., 2006;Mano et al., 2007). Themetabolite acts as amechanism-based inhibitor of CYP2C8, with inhibitor concentra-tion supporting half of the maximal rate of enzymeinactivation (KI) and maximal rate of inactivation (kinact)values of 20–52 mM and 0.21 1/min in vitro (Ogilvieet al., 2006; Baer et al., 2009). Similarly, clopidogrel acyl1-b-D-glucuronide causes a metabolism-dependent in-hibition of CYP2C8 with KI and kinact values of 9.9 mMand 0.047 1/min (Tornio et al., 2014). The in vivoconsequences of the inhibitory effects of these metabo-lites are discussed in section VI. In an in vitro studyby Jenkins et al. (2011), the acyl glucuronides of ator-vastatin, dehydroketoprofen, diclofenac, ibuprofen,indomethacin, rac-ketoprofen, mefenamic acid, R- andS-naproxen, and simvastatin did not affect CYP2C8 bymetabolism-dependent inhibition.

Several other metabolism-dependent inhibitors ofCYP2C8 have been reported in the literature (Table 8).However, the clinical importance of their interactionpotential is unknown.

C. Induction

Increased expression of CYP2C8 protein in hepato-cytes due to enzyme-inducing drugs/xenobiotics is animportant mechanism of drug-drug interactions thatcan lead to markedly increased clearance of CYP2C8substrates, resulting in reduced efficacy and therapeu-tic failure. Several drug-responsive nuclear receptors,including CAR, PXR, VDR, and GR, can mediate thetranscriptional activation of the CYP2C8 gene byrecognizing the respective responsive elements withinthe 59-flanking promoter region of the gene (Chen andGoldstein, 2009). After activation of nuclear receptorsby their ligands/activators (in particular, enzyme in-ducing drugs), the nuclear receptors enter the nu-cleus, bind to their responsive elements in the DNA,recruit coactivators that affect chromatin structure,

210 Backman et al.

TABLE

8Metab

olism-dep

ende

ntCYP2C

8inhibitors

invitro

Inhibitor

Therap

euticUse

and/or

Dru

gClass

Mod

eof

Inhibition

Preinc.

IC50a

IC50Shiftb

KI

k inact

Test

System

Marke

rRea

ctionc

Referen

ces

mM

ratio

mM

1/min

17a-E

thinylestrad

iol

Con

tracep

tive

,hormon

ede

riva

tive

8.3

1.9

HLM

Pacli

Cha

nget

al.,20

09Amioda

rone

Antiarrh

ythmic

1.5

0.07

9rC

YP2C

8Pacli

Polas

eket

al.,20

0451

.20.02

9HLM

Pacli

Polas

eket

al.,20

04Bosutinib

Anticanc

er,PKI

16.9

2.6

54.8

0.01

8HLM

Amo

Filpp

ulaet

al.,20

14Clopido

grel

acyl

1-b-D

-glucu

ronide

Dru

gmetab

olite

12.0

4.7

9.9

0.04

7HLM

Amo

Tornioet

al.,20

14

Desethy

lamioda

rone

Dru

gmetab

olite

0.67

3.3

4.4

0.00

9HLM

Amo

Oba

chet

al.,20

07Dem

ethylda

brafen

ibDru

gmetab

olite

30a

1.6

HLM

Rosi

Law

renc

eet

al.,20

14Fluox

etine

Antidep

ressan

t,SSRI

Qua

si-irrev

ersible

294

0.08

3rC

YP2C

8Pacli

Polas

eket

al.,20

04Gem

fibrozil1-O-b

gluc

uron

ide

Dru

gmetab

olite

Irreve

rsible

1.8

13.3

20-52

0.21

HLM

Pacli

Ogilvie

etal.,20

06

4.51

0.10

6Hep

n/a

Neg

ishi

etal.,20

0729

0.07

2rC

YP2C

8Amo

Bae

ret

al.,20

090.46

98HLM

Amo

Perloffet

al.,20

093.0

HLM

Mon

teKaron

enet

al.,20

104.5

HLM

Mon

te-4

Karon

enet

al.,20

100.26

0.01

5HLM

Amo

Ten

get

al.,20

101.4

16HLM

Amo

Jenk

inset

al.,20

1110

.10.04

1HLM

Amo

Van

denB

rink

etal.,20

1121

.30.05

0HLM

Mon

teVan

denB

rink

etal.,20

1135

0.02

2HLM

Pacli

Van

denB

rink

etal.,20

1133

.60.08

2HLM

Pio

Van

denB

rink

etal.,20

1118

.40.03

5HLM

Rep

aVan

denB

rink

etal.,20

1148

.50.07

1HLM

Rosi

Van

denB

rink

etal.,20

1110

.34–

25.4

0.10

4–0.25

HLM

Amo

Korzekw

aet

al.,20

14Gem

fibrozild 6-1-O

-bglucu

ronide

Dru

gmetab

olite,

Deu

terated

290.03

3rC

YP2C

8Amo

Bae

ret

al.,20

09

Ison

iazid

Antitube

rculosis

Qua

si-irrev

ersible

374

0.04

2rC

YP2C

8Pacli

Polas

eket

al.,20

0417

00.01

2HLM

Pacli

Polas

eket

al.,20

04LuAA34

893carbam

oyl

glucu

ronide

Dru

gMetab

olite

8.5

8.4

HLM

n/a

Kaz

miet

al.,20

10

O-m

ethy

lgem

fibrozil

acyl-b- D-glucu

ronide

Gem

fibrozilAcyl-b-D-glucu

ronideAna

log

173.2

HLM

Amo

Jenk

inset

al.,20

11

Nortriptyline

Antidep

ressan

t,TCA

Qua

si-irrev

ersible

49.9

0.03

6rC

YP2C

8Pacli

Polas

eket

al.,20

04Phen

elzine

Antide

pressa

nt,MAOI

1.2

0.24

3rC

YP2C

8Pacli

Polas

eket

al.,20

0454

.30.17

HLM

Pacli

Polas

eket

al.,20

04Ralox

ifen

eAntiosteope

rotic,

SERM

.2

0.26

0.1

rCYP2C

8Pacli

Van

denB

rink

etal.,20

12Thu

jops

ene

Sesqu

iterpe

ne29

.83.3

HLM

Amo

Jeon

get

al.,20

14Torem

ifen

eAntican

cer,

SERM

5.0

1.9

HLM

Pacli

Kim

etal.,20

11b

Verap

amil

Antihyp

ertens

ive,

CCB

Qua

si-irrev

ersible

17.5

0.06

5rC

YP2C

8Pacli

Polas

eket

al.,20

04

CCB,calcium

chan

nel

blocke

r;Hep

,hep

atocytes:H

LM,h

uman

live

rmicrosomes;I

C50,inhibitor

concentrationsu

pporting

halfof

themax

imal

inhibition;K

I,inactiva

tion

constan

t;k i

nact,m

axim

alrate

ofinactiva

tion

;MAOI,

mon

oamineox

idas

einhibitor;n/a,not

available;

PKI,

protein

kinas

einhibitor;rC

YP2C

8,recombina

ntCYP2C

8,SERM,selectiveestrog

enreceptor

mod

ulator;

SSRI,

selectiveserotonin

reuptak

einhibitor;TCA,tricyclic

antide

pressa

nt.

aPreinc.

IC50de

pictsIC

50afterpr

eincu

bation

ofinhibitor

for30

min

withNADPH

before

addition

ofsu

bstrate,

except

inthecase

ofde

methylda

brafen

ibwherethepr

eincu

bation

timewas

20min.

bIC

50sh

ift=reve

rsible

IC50/preinc.

IC50.A

nIC

50sh

ift$1.5-fold

isindicative

ofmetab

olism-dep

ende

ntinhibition.

c Amo,

amod

iaqu

ineN-dee

thylation;M

onte,m

onteluka

st36

-hyd

roxy

lation

;Mon

te-4,formationof

mon

teluka

stM4;

Pacli,p

aclitaxe

l6a-hyd

roxy

lation

;Pio;p

ioglitaz

onehyd

roxy

lation

(M-IV);Rep

a,repa

glinide39-hyd

roxy

lation

;Rosi,rosiglitaz

oneN-dem

ethylation.


and increase the transcription of the target genes(Handschin and Meyer, 2003). Apart from this generalmechanism, certain compounds, such as phenobarbitaland CITCO ([6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime),seem to cause induction by increasing the nucleartranslocation of CAR, which is constitutively active(Zelko et al., 2001). Other nuclear receptors and tran-scriptional factors, such as HNF4a, HNF3g, C/EBPa,and RORs, can regulate the constitutive expression ofCYP2C genes, but these factors are probably not di-rectly involved in induction of CYP2C8 (Ferguson et al.,2005; Chen and Goldstein, 2009; Rana et al., 2010). Yet,at leastHNF4a seems to be required for upregulation bythe PXR agonist rifampin (Rana et al., 2010).In experimental in vitro studies, several compounds

and ligands of the different nuclear receptors have beenable to induce CYP2C8 (Table 9). On the basis of studiesin cultured human hepatocytes, CYP2C8 is the mostinducible member of the CYP2C subfamily (Gerbal-Chaloin et al., 2001; Feidt et al., 2010). Regardinginducibility of CYP2C8, the PXR-receptor seems to bethe most important nuclear receptor, because typicalPXR ligands/activators strongly induce CYP2C8 in vitro(Ferguson et al., 2005; Chen and Goldstein, 2009) andcan cause induction of CYP2C8 also in vivo, whereasligands of the other nuclear receptors cause only moder-ate induction of CYP2C8 in vitro (Ferguson et al., 2005;Chen and Goldstein, 2009) and have not been shown tomarkedly induce CYP enzymes in vivo in humans. PXRactivators, such as phenobarbital, hyperforin (an in-gredient of St. John’swort), and rifampin, have increasedCYP2C8 expression at mRNA, protein, and activitylevels several-fold in vitro (Dussault et al., 2001;Gerbal-Chaloin et al., 2001; Rae et al., 2001; Nishimuraet al., 2002; Raucy et al., 2002; Madan et al., 2003;Ferguson et al., 2005; Komoroski et al., 2005; Thomaset al., 2015). In addition, certain other compounds,including ritonavir, nelfinavir, cyclophosphamide, lith-ocholic acid, and paclitaxel can induce CYP2C8 pre-sumably by a PXR-mediatedmechanism in vitro (Changet al., 1997; Dussault et al., 2001; Synold et al., 2001;Ferguson et al., 2005; Dixit et al., 2007). It should benoted that in one study, rifampin induced CYP2C8mRNA in only three of the eight commercially availablecryopreserved hepatocyte lots tested (Yajima et al.,2014), suggesting that cryopreserved hepatocytes maynot be a reliable system for studying CYP2C8 induction.Apart from PXR, induction of CYP2C8 can be exper-

imentally achieved at least via CAR- and GR-mediatedand possibly also via VDR- and PPAR-alpha-mediatedmechanisms (Ferguson et al., 2005; Chen and Goldstein,2009). The CAR-agonists phenytoin and CITCO havemarkedly induced CYP2C8 expression in human hepa-tocytes (Ferguson et al., 2005). In addition, dexameth-asone (GR agonist) can modestly increase CYP2C8expression in in vitro systems (Gerbal-Chaloin et al.,

2001; Rae et al., 2001; Raucy et al., 2002; Madan et al.,2003; Ferguson et al., 2005). Moreover, VDR maybe involved in the induction of CYP2C8 by lithocholicacid in HepG2 cells (Makishima et al., 2002; Yajimaet al., 2014), and the PPAR-alpha-agonist WY14,643(4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid)has induced CYP2C8 mRNA in HepaRG cells (Thomaset al., 2015). In addition to the above compounds,certain other drugs have weakly induced CYP2C8 invitro with unknown induction mechanisms, includingtasimelteon and crizotinib (FDA, 2011e,m; EMA, 2012c;TGA, 2014).

In humans in vivo, rifampin has markedly reducedthe plasma exposure to several CYP2C8 substrates(Jaakkola et al., 2006a; Niemi et al., 2000; Niemiet al., 2004a; Park et al., 2004), and it is consequentlythe preferred CYP2C8 inducer drug for use in clinicalstudies (section VII). Yet, the strength of the CYP2C8inducing effect of rifampin (or any other PXR ligands)has been difficult to estimate, because the strongCYP3A4-inducing effect of rifampin is likely to partiallyexplain its effects on the clearance of CYP2C8 sub-strates. Of note, one of the strongest clinical inducers ofCYP enzymes, carbamazepine, which is also a weakPXR activator, seems to be poorly characterized withregard to CYP2C8 both in vitro and in vivo.

VI. Clinical Drug Interactions Mediated viaCytochrome P450 2C8

A. General Aspects

The CYP2C8 enzyme is involved in many drug-druginteractions in humans, including interactions basedon either inhibition or induction of CYP2C8. However,its exact role in interactions is difficult to determine,because there are no fully selective in vivo inhibitorsor inducers of CYP2C8 and all known CYP2C8 sub-strates aremetabolized, at least to a small degree, also byother enzymes. Furthermore, the activities of OATP1B1,P-glycoprotein or other membrane transporters canaffect the pharmacokinetics of many CYP2C8 substratedrugs, and some inhibitors of CYP2C8 inhibit thesetransporters, too. Because drug metabolizing enzymesand transporters may influence drug metabolism inconcert, the isolated role of CYP2C8 in many drug-druginteractions can be very difficult to dissect in vivo.

The clinical significance of pharmacokinetic drug-drug interactions depends both on the therapeutic indexof victim drug and on the extent of pharmacokineticchanges, in addition to various patient-related clinicalfactors. Of the pharmacokinetic parameters, at least theplasma AUC, peak concentration (Cmax), time to max-imum concentration (tmax), and elimination half-life (t1/2)values are generally required for the characterizationof an interaction. Here, to be brief, we usually reportonly fold-changes of the mean AUC values causedby interactions. Of note, e.g., interindividual genetic

212 Backman et al.

TABLE 9Some inducers of CYP2C8 in vitro

Inducer Therapeutic Useand/or Drug Class CYP2C8 mRNA CYP2C8 Protein in

HepatocytesCYP2C8 Activityin Hepatocytes References

CITCO 2.5-fold in primary hepatocytes Ferguson et al., 20051-fold in primary hepatocytes Thomas et al., 2015

Clofibric acid Antihyperlipidemic 2-to 3-fold in primaryhepatocytes

Prueksaritanontet al., 2005

Cyclophosphamide Anticancer, alkylating agent + Chang et al., 1997Dexamethasone Anti-inflammatory,

glucucortidcoid+ Chang et al., 1997

3-fold in primary hepatocytes 2-fold Gerbal-Chaloinet al., 2001

5-fold in primary hepatocytes 4-fold Raucy et al., 2002,2-fold in primary hepatocytes Ferguson et al., 2005

Fenofibric acid Antihyperlipidemic 2- to 6-fold in primaryhepatocytes


Gemfibrozil Antihyperlipidemic,PPARa agonist

1.1- to 5-fold in primaryhepatocytes


Hyperforin Constituent of St. John’swort

+ in primary hepatocytes Dussault et al., 2001

5-fold in primary hepatocytes Ferguson et al., 2005+ Komoroski et al., 2005

Idelalisib Anticancer, PKI 3.9-fold in human hepatocytes FDA, 2014hIdelalisib metabolite

GS-563117Drug metabolite 1.4-fold in human hepatocytes FDA, 2014h

Ifosfamide Anticancer, alkylating agent + Chang et al., 1997Lithocholic acid Bile acid ,2-fold in primary hepatocytes Ferguson et al., 2005Nelfinavir Antiviral, protease inhibitor 5-fold in primary hepatocytes 2-fold Dixit et al., 2007Nilotinib Anticancer, PKI No induction of CYP2C8

mRNA.2-fold FDA, 2007c

Paclitaxel Anticancer, taxane 4-fold in primary hepatocytes Ferguson et al., 2005+ in primary hepatocytes Synold et al., 2001

Phenobarbital Antiepileptic, barbiturate + Chang et al., 19973-fold in primary hepatocytes 3-fold Gerbal-Chaloin

et al., 20017-fold in primary hepatocytes Raucy et al., 2002

3- to 6-fold Madan et al., 20032-fold in primary hepatocytes Ferguson et al., 2005

Phenytoin Antiepileptic 2-fold in primary hepatocytes Ferguson et al., 2005Progesterone Hormonal replacement

therapy1.4- to 9.2-fold in primary

hepatocytesChoi et al., 2013

Rifampin(rifampicin)

Antibiotic + Chang et al., 1997

6-fold in primary hepatocytes 3-fold Gerbal-Chaloinet al., 2001

6.5-fold in primary hepatocytes Rae et al., 2001+ in primary hepatocytes Dussault et al., 2001+ in primary hepatocytes Synold et al., 20017- to 12-fold in primary

hepatocytes6-fold (1- to 17-fold) Raucy et al., 2002

4- to 8-fold in primaryhepatocytes

Madan et al., 2003

3-fold in primary hepatocytes 3- to 10-fold Ferguson et al., 20054- to 9-fold in primary

hepatocytesPrueksaritanont

et al., 20057-fold in primary hepatocytes 4-fold Dixit et al., 20076.5-fold in primary hepatocytes Rana et al., 20100.7- to 3-old in primary

hepatocytesYajima et al., 2014

5-fold in HepaRG cells Thomas et al., 2015Ritonavir Antiviral, protease inhibitor + in primary hepatocytes Dussault et al., 2001

+ in primary hepatocytes Synold et al., 20017-fold in primary hepatocytes 2-fold Dixit et al., 2007

SR12813 Antihyperlipidemic,HMG-CoAreductase inhibitor

+ in primary hepatocytes Synold et al., 2001

Tasimelteon Circadian regulator 4.4-fold FDA, 2014mWY14,643 Antihyperlipidemic,PPARa

agonist4-fold in HepaRG cells Thomas et al., 2015

CITCO, [6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; PKI, proteinkinase inhibitor, HepaRG, hepatocyte-like cells from the human hepatoma HepaRG cell line; mRNA, messenger RNA; PPAR, peroxisome proliferator-activated receptor;SR12813, tetraethyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethenyl-1,1-bisphosphonate; WY14,643, 4-Chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid.


variation in the activity of drug metabolizing enzymesand transporters can cause a considerable variability inthe extent of drug interactions. In particular, it isimportant to note that in an individual patient theexposure to a victim drug can change much more thanthe generally reported mean change.Recognition of the role of CYP2C8 as an important

oxidative enzyme in drugmetabolismhas led to changes inproduct information of many drugs, resulting in betterpredictability of their interactions and improved safety. Insome cases, CYP2C8-mediated drug interactions and theresultant adverse effects have forced the manufacturersto withdraw drugs from clinical use or to add contraindi-cations or limitations to their use. In general, specialattention is needed, if a drug with narrow safety margin isextensivelymetabolized by CYP2C8 or if a drug is a strongCYP2C8 inhibitor like gemfibrozil and clopidogrel. Inaddition, it should be recognized that rifampin and someotherpotent enzyme inducers canmarkedly reduceplasmaconcentrations and effects of CYP2C8 substrate drugs.As gemfibrozil is a well-characterized inhibitor of

CYP2C8 that has increased the plasma concentrationsof several drugs (Fig. 7; Table 10), we first present adetailed description of it as an in vivo inhibitor in thefollowing part. The other clinically relevant CYP2C8inhibitors, including clopidogrel, trimethoprim, efavirenz,and teriflunomide (Niemi et al., 2004b; Germanet al., 2007; FDA, 2012a; Tornio et al., 2014), are dealtwith in the next part, where we focus on the CYP2C8-inhibition-mediated drug interactions of differenttherapeutic CYP2C8 substrate drugs. Thereafter, wepresent CYP2C8 induction-mediated drug interactionsand their clinical relevance.

B. Gemfibrozil as Prototypical Inhibitor

1. In Vitro Versus In Vivo. In vitro, the parentgemfibrozil is a moderately potent competitive inhibitorof CYP2C9 (Ki value of 5.8 mM;Wen et al., 2001), but it isover 10 times less potent as inhibitor of CYP2C8 (Ki valueof 75 mM, Wang et al., 2002; Ki 87 mM, Prueksaritanontet al., 2002; Table 6). Gemfibrozil in concentrations up to1,000 mM has no effect on CYP3A4 activity (midazolam19-hydroxylation) (Backman et al., 2000), but it is ratherpotent as an inhibitor of theOATP1B1 transporter, with aKi value ranging in different studies from 4 to 31.7 mM(Schneck et al., 2004; Yamazaki et al., 2005; Hirano et al.,2006; Nakagomi-Hagihara et al., 2007).

In healthy volunteers, gemfibrozil (600 mg twice daily)slightly (by 23%) increased the AUC of a CYP2C9substrate drug glimepiride (Niemi et al., 2001) but didnot increase the exposure to racemic warfarin (Liljaet al., 2005). Gemfibrozil even caused a small butstatistically significant decrease (211%) in the AUC ofthe CYP2C9 substrate S-warfarin. These results stronglysuggest that gemfibrozil is not a meaningful inhibitorof CYP2C9 in vivo in humans.

In vivo gemfibrozil is glucuronidated by the UGT 2B7enzyme to gemfibrozil 1-O-b-glucuronide. The benzylicoxidation of the glucuronide by CYP2C8 leads to haemalkylation and irreversible inactivation of CYP2C8(Baer et al., 2009; Jenkins et al., 2011). In HLM, thekinact value of CYP2C8 by gemfibrozil 1-O-b-glucuronidehas been 0.21 1/min and KI 20–52 mM (Ogilvie et al.,2006). The glucuronide metabolite is also a competitiveinhibitor of OATP1B1 (OATP2) transporter (Ki 24 mM;Shitara et al., 2004). On the basis of clinical studies on

Fig. 7. Effects of gemfibrozil on the exposure (area under the plasma drug concentration-time curve) to different CYP2C8 substrate drugs. The effect ofgemfibrozil on drug exposures may also include inhibition of OATP1B1 (cerivastatin acid, lovastatin acid, paritaprevir, repaglinide, and simvastatinacid). Dasabuvir and paritaprevir were administered as a dasabuvir-paritaprevir-ritonavir combination. A fold increase of 1 refers to no effect ofgemfibrozil on drug exposure. References are given in Table 10.

214 Backman et al.

TABLE 10Drug-drug interactions caused by CYP2C8-inhibiting drugs in humans

Inhibitor Dosing Substrate AUC Change References

foldAtazanavir 400 mg once daily for 6 days, substrate on day 6 Rosiglitazone 1.4 FDA, 2015bClopidogrel 75–300 mg for 3 days, substrate on days 1 and 3 Repaglinide 3.9–5.1a Tornio et al., 2014Deferasirox 30 mg/kg once daily for 3 days, substrate on day 4 Repaglinide 2.3b Skerjanec et al., 2010Efavirenz 400 mg once daily for 12 days, substrate on day 9 Amodiaquine 1.8 Soyinka et al., 2013

Active metabolite:N-desethylamodiaquine

0.7 Soyinka et al., 2013

Enzalutamide 160 mg once daily for 97 days, substrate on day 42 Pioglitazone n.s. (1.2) Gibbons et al., 2015Active metabolite:hydroxypioglitazone (M-IV)

0.63 Gibbons et al., 2015

Gemfibrozil 600 mg twice daily for 6 days, substrate on day 6 Alogliptin 1.1b FDA, 2013gActive metabolite: M-I 1.9b FDA, 2013g

600 mg twice daily for 7 days, substrate on day 4 Brivaracetam 1.0 Nicolas et al., 2012600 mg twice daily for 3 days, substrate on day 3 Cerivastatin (acid) 5.6a Backman et al., 2002

Cerivastatin lactone 4.4 Backman et al., 2002600 mg twice daily for 4 days, substrate on day 4 Dabrafenib 1.5 Suttle et al., 2015600 mg twice daily for 5 days, substrate on day 4 Daprodustat (GSK1278863A) 18.6 Johnson et al., 2014600 mg twice daily for 5 days, substrate on day 3 Dasabuvir (ABT-333)b 11.3 Menon et al., 2015

Active metabolite:dasabuvir M1

0.22 Menon et al., 2015

600 mg twice daily for 21 days, substrate on day 4 Enzalutamide 4.3 Gibbons et al., 2015Active metabolite:N-demethylenzalutamide

0.75 Gibbons et al., 2015

600 mg twice daily for 7 days, substrate for 7 days Ezetimibe 1.4b Reyderman et al., 2004600 mg twice daily for 3 days, substrate on day 3 R-Ibuprofen 1.3 Tornio et al., 2007600 mg twice daily for 6 days, substrate on day 3 Imatinib n.s. Filppula et al., 2013b

Active metabolite:N-demethylimatinib

0.5 Filppula et al., 2013b

600 mg twice daily for 5 days, substrate on day 3 Loperamide 2.2 Niemi et al., 2006600 mg twice daily for 3 days, substrate on day 3 Montelukast 4.6 Karonen et al., 2010

Active metabolite: 36-hydroxymontelukast (M6)

0.6c Karonen et al., 2010

Montelukast 4.3 Karonen et al., 2011Active metabolite: 36-hydroxymontelukast (M6

0.6c Karonen et al., 2011

600 mg twice daily for 5 days, substrate on day 3 Paritaprevir (ABT-450)d 1.4a Menon et al., 2015600 mg twice daily for 3 days, substrate on day 3 Pioglitazone 3.4 Deng et al., 2005

Active metabolite:hydroxypioglitazone (M-IV)

n.s. Deng et al., 2005

Active metabolite:ketopioglitazone (M-III)

n.s. Deng et al., 2005

600 mg twice daily for 4 days, substrate on day 3 Pioglitazone 3.2 Jaakkola et al., 2005Active metabolite:ketopioglitazone (M-III)

0.6 Jaakkola et al., 2005

Active metabolite:hydroxypioglitazone (M-IV)

0.6 Jaakkola et al., 2005

600 mg twice daily for 4 days, substrate on day 3 Pioglitazone 4.3 Aquilante et al., 2013a600 mg twice daily for 3 days, substrate on day 3 Repaglinide 8.1a Niemi et al., 2003b600 mg twice daily for 3 days, substrate on day 3 7.3-8.3a Kalliokoski et al., 2008b600 mg twice daily for 3 days, substrate on day 3 7.0a Tornio et al., 2008a600 mg twice daily for 3 days, substrate on days 3-6 1.0-7.6a Backman et al., 2009A single dose of 30-900 mg 1 h prior to substrate

intake1.8-8.3a Honkalammi et al., 2011a

A single dose of 600 mg 0-6 h prior to substrateintake

5.0-6.6a Honkalammi et al., 2011b

30–600 mg twice daily for 5 days, substrate on day 5 3.4-7.0a Honkalammi et al., 2012600 mg twice daily for 4 days, substrate on day 3 Rosiglitazone 2.3 Niemi et al., 2003a600 mg twice daily for 3 days, substrate on day 3 Simvastatin (lactone) 1.4 Backman et al., 2000

Simvastatin acid 2.9a Backman et al., 2000600 mg twice daily for 3 days, substrate on day 4 Sitagliptin 1.5e Arun et al., 2012600 mg twice daily for 4 days, substrate on day 3 Treprostinil 1.9 FDA, 2009b600 mg twice daily for 8 days, substrate on day 3 R-Warfarin 0.9 Lilja et al., 2005.

S-Warfarin 0.9 Lilja et al., 2005.600 mg twice daily for 3 days, substrate on day 3 Zopiclone n.s. Tornio et al., 2006

N-demethylzopiclone 1.2 Tornio et al., 2006N-oxide-zopiclone 2.0 Tornio et al., 2006

Teriflunomidef 14–70 mg once daily for 12 days, substrateon day 12

Repaglinide 2.3a FDA, 2012a

Trimethoprim 960 mg (combination)g twice daily for 6 days,substrate on day 6

Amodiaquine 1.6 Akande et al., 2015

Active metabolite:N-desethylamodiaquine

0.9 Akande et al., 2015

160 mg twice daily for 3 days, substrate on day 3 Cerivastatin (acid) 1.4 Backman et al., 2003Cerivastatin lactone 1.5 Backman et al., 2003

(continued )


the dose/time dependency of the effect of gemfibrozil onthe pharmacokinetics of repaglinide and statisticalmodels of enzyme and transporter inhibition, it hasbeen estimated that the in vitro mechanism-basedinhibition of CYP2C8 by gemfibrozil 1-O-b-glucuronidemanifests into a strong and long-lasting inhibitionof CYP2C8 at typical clinical doses of gemfibrozil(Backman et al., 2009; Honkalammi et al., 2011a,b). Inaddition, the OATP1B1 inhibitory effect of the glucuro-nide can lead to an up to ;50% transient inhibition ofOATP1B1 in vivo. These effects are the main explana-tion to the effects of gemfibrozil on CYP2C8 andOATP1B1 substrates (Honkalammi et al., 2012). Sim-ilar estimations have been obtained with physiologi-cally based pharmacokinetic modeling in a recentpublication (Varma et al., 2015).2. Gemfibrozil Dose Versus CYP2C8 Inhibition.

Single oral doses of gemfibrozil, i.e., 30, 100, 300, or 900mg ingested 1 hour before repaglinide, increased theAUC of repaglinide in a dose-dependent manner 1.8-,4.5-, 6.7-, and 8.3-fold compared with placebo, respectively(Fig. 8; Honkalammi et al., 2011a). Also after multipledoses of gemfibrozil (30, 100, or 600 mg twice daily for5 days), the exposure to repaglinide increased dosedependently, but the greatest AUC increase did notexceed that observed after the single 900 mg gemfibrozildose (Honkalammi et al., 2012). Thus, the maximuminhibition of CYP2C8 can be achieved by a single 900-mgdose of gemfibrozil (Fig. 9). Gemfibrozil in doses of 100mg twice daily at steady state causes an about 95%inhibition of CYP2C8 (Fig. 9), and in doses of 10mg twicedaily, it causes an about 50% inhibition (Honkalammiet al., 2011a). The fraction of a small 0.25-mg dose ofrepaglinide metabolized by CYP2C8 is about 80–90%.However, because repaglinide is metabolized to someextent also by CYP3A4, the relative role of CYP2C8 andCYP3A4 in the biotransformation of repaglinide candepend on its dose and plasma concentrations as wellas on individual pharmacogenetic factors (Bidstrup et al.,2003; Kajosaari et al., 2005a; Säll et al., 2012).3. Onset and Duration of CYP2C8 Inhibition by

Gemfibrozil. The onset and duration of CYP2C8

inhibition by gemfibrozil have been studied in healthyvolunteers using the gemfibrozil-repaglinide interac-tion as a model. Single 600-mg doses of gemfibrozilingested 0, 1, 3, or 6 hours before repaglinide (0.25 mg)increased the geometric mean AUC of repaglinide 5.0-,6.3-, 6.6-, and 5.4-fold, respectively (Fig. 8). The Cmax ofthe CYP2C8-mediated repaglinide M4-metabolite was1.0-, 0.10-, 0.06-, and 0.09-fold compared with controlphase, respectively (Honkalammi et al., 2011b). Theseresults indicate that the strong inactivation of CYP2C8occurs rapidly, being evident alreadywithin 1 hour afteroral dosing of gemfibrozil.

When repaglinide was ingested 1, 24, 48, or 96 hoursafter discontinuation of a gemfibrozil treatment (600 mgtwice daily for 3 days), the AUC of repaglinide was7.6-, 2.9-, 1.4-, and 1.0-fold compared with the controlphase, respectively (Backman et al., 2009). Thesefindings confirmed and extended the previous findings,which had shown that the inhibitory effect of gemfibro-zil persists for at least 12 hours after its ingestion(Tornio et al., 2008a). As the half-lives of gemfibroziland its glucuronide are very short (about 1–2 hours),these findings convincingly demonstrate that the effectof gemfibrozil on repaglinide pharmacokinetics is basedon irreversible mechanism-based inhibition of CYP2C8.A several-fold increase in repaglinide AUC was evidenteven at very low plasma concentrations of gemfibrozil1-O-b-glucuronide, which are less than 1% of its peakconcentrations. The results also showed that fullCYP2C8 activity recovers gradually within 3–4 daysafter cessation of the clinically used therapeutic doses of600 mg twice daily gemfibrozil.

4. Quantification of CYP2C8-Mediated Drug Interac-tions in Humans. Interactions caused by a combina-tion of two or more drugs, which inhibit, in addition toCYP2C8, also some other crucial enzyme or transporter,can increase exposure to a CYP2C8 substrates muchmore than is the sum of their separate effects causing aclassic potentiation phenomenon. Thus, e.g., exposureto repaglinide is increased only slightly by itraconazolealone (1.4-fold), greatly by gemfibrozil alone (8.1-fold),and drastically (19.4-fold) by their combination (Fig. 10;

TABLE 10—Continued

Inhibitor Dosing Substrate AUC Change References

960 mg (combination)g twice daily for 3 days, substrateon day 2

Loperamide 1.9 Kamali and Huang, 1996

160 mg twice daily for 6 days, substrate on day 3 Pioglitazone 1.4 Tornio et al., 2008bActive metabolite:hydroxypioglitazone (M-IV)

1.1 Tornio et al., 2008b

160 mg twice daily for 3 days, substrate on day 3 Repaglinide 1.6 Niemi et al., 2004b160 mg twice daily for 4 days, substrate on day 3 Rosiglitazone 1.4 Niemi et al., 2004a200 mg twice daily for 5 days, substrate on day 5 1.3 Hruska et al., 2005

AUC, area under the plasma concentration-time curve; n.s. not statistically significant.aInhibition of OATP1B1 may also be involved.bThe role of CYP2C8 in the interaction is limited or unclear.cAUC0–7 hour.dGiven as a dasabuvir-paritaprevir-ritonavir combination.eInhibition of OAT3 may also be involved.fOf note, teriflunomide is the active metabolite of leflunomide. Hence, coadministration of leflunomide with CYP2C8 substrate drugs may also cause interactions.gTrimethoprim was given in a combination with sulfaphenazole (cotrimoxazole).

216 Backman et al.

Niemi et al., 2003b). The quantitative rationalization ofgemfibrozil-drug interactions and consideration oftransporter-enzyme interplay have been dealt quiterecently by Varma et al. (2015).

C. Inhibition-Mediated Drug Interactions and TheirClinical Significance

1. Repaglinide. Interactions of the oral antidiabeticdrug repaglinide have been studied extensively, and itis a recommended model substrate drug for CYP2C8 in-teraction studies (EMA, 2012b; http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm). In healthyvolunteers, gemfibrozil (600 mg twice daily for 3 days)raised the AUC of repaglinide 8.1-fold, itraconazoleraised it 1.4-fold, and their combination raised it19.4-fold (Niemi et al., 2003b). Gemfibrozil alone andin combination with itraconazole considerably enhanced

also the blood glucose lowering effect of repaglinide(Niemi et al., 2003b). This pioneering study clearlyindicated that the extent of interaction caused by acombination of two drugs can greatly exceed the sum oftheir separate effects. On the basis of these results andclinical observations of serious hypoglycemic episodesin diabetic patients, The European Agency for theEvaluation of Medicinal Products gave “EMEA publicstatement on repaglinide contraindication of concomi-tant use of repaglinide and gemfibrozil” (21.05.2003).Also the U.S. Food and Drug Administration warnedagainst repaglinide-gemfibrozil interaction. The effectof gemfibrozil on repaglinide exposure was laterconfirmed and characterized in several studies as de-scribed in previous paragraphs (sections VI.B.1–3). Thegemfibrozil-repaglinide interaction is mainly mediatedvia inhibition of CYP2C8 and OATP1B1 by the gemfi-brozil 1-O-b-glucuronide.

Fig. 8. Effects of gemfibrozil on the exposure (area under the plasma drug concentration-time curve) to repaglinide (Repa) and its metabolites M1, M2,and M4. Fold changes in drug exposure compared with the control phase when repaglinide was taken 1 hour after a single 30-, 100-, 300-, or 900-mgdose of gemfibrozil (A) or 1 hour after the last dose of 30, 100, or 600 mg gemfibrozil twice daily (B). Fold changes in drug exposure as compared with thecontrol phase, when a single 600-mg dose of gemfibrozil was taken simultaneously or 1, 3, or 6 hours before repaglinide intake (C) or when the last doseof gemfibrozil was taken 0, 1, 3, 6, 12, 24, 48, or 96 hours before repaglinide intake (D). For M4, AUC0-3 hour data are presented. For all othercompounds, AUC0-‘ data are presented. A fold change of 1 refers to no effect of gemfibrozil on exposure. References are given in the text.





The antimicrobial drug trimethoprim (160 mg twicedaily for 3 days) raised in healthy volunteers the AUC ofrepaglinide by 1.6-fold compared with placebo (Niemiet al., 2004b). Symptomatic hypoglycemia developed ina diabetic patient 5 days after addition of trimethoprim/sulfamethoxazole therapy to his previously well-toleratedrepaglinide (1 mg three times daily) treatment (Roustitet al., 2010).The 300-mg loading dose of clopidogrel raised the

AUC of repaglinide by 5.1-fold, and the following daily75-mg doses of clopidogrel raised the AUC by 3.9-foldin healthy volunteers (Tornio et al., 2014). The increasein repaglinide AUC caused by clopidogrel was highest insubjects with the CYP2C8*1/*4 genotype (Tornio et al.,2014). The clopidogrel-repaglinide interaction is medi-ated by formation of the clopidogrel acyl-b-D-glucuronide,which is a potent time-dependent inhibitor of CYP2C8.On the basis of this short-term study, it has beenextrapolated that the daily treatment with 75 mg ofclopidogrel causes a continuous, 60–85% inhibition ofhepatic CYP2C8 under steady-state conditions duringchronic clopidogrel use. The pharmacokinetic interactionof clopidogrel and repaglinide resulted in an enhancedblood glucose-lowering effect of repaglinide. The con-comitant use of repaglinide and clopidogrel is now

contraindicated, e.g., in Canada (http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2015/54454a-eng.php).

The immunosuppressant teriflunomide (70 mg oncedaily for 4 days, followed by 14 mg once daily for 8 days)increased the AUC of repaglinide by 2.3-fold in healthymale subjects (FDA, 2012a) compared with whenrepaglinide was given alone. In three subjects theAUC was raised by 3.2- to 3.6-fold. Teriflunomideinhibits both CYP2C8 and OATP1B1, and the contri-bution of each mechanism to the increase in repaglinideexposure has not been established (FDA, 2012a). Ofnote, teriflunomide is the active metabolite of lefluno-mide and its plasma concentrations following lefluno-mide administration are equal to those observed whenit is given alone. Hence, leflunomide may also be aclinically relevant CYP2C8 inhibitor.

Care is warranted if inhibitors of CYP2C8 arecombined with repaglinide. In particular, combinationof strong CYP2C8 inhibitors, such as gemfibrozil andclopidogrel, with repaglinide should be avoided. Bloodglucose levels and symptoms of hypoglycemia should bemonitored closely and the doses modified as needed.The interactions with repaglinide are likely to bestronger in CYP2C8*3 carriers than in CYP2C8*1homozygotes (Tornio et al., 2008a).

2. Other Oral Antidiabetic Drugs. The Europeanproduct information of Actos (pioglitazone) stated ear-lier (e.g. 2004) that metabolism of pioglitazone occurspredominantly via CYP3A4 and CYP2C9 (Jaakkolaet al., 2005), whereas the U.S. label stated that the majorCYP isoforms involved were CYP2C8 and CYP3A4(FDA, 1999). The in vitro study of Jaakkola et al.(2006c) showed that pioglitazone is metabolized mainly

Fig. 10. Effects of gemfibrozil (Gem), itraconazole (Itra), or theircombination (Gem + itra) on the exposure (area under the plasma drugconcentration-time curve) to repaglinide, loperamide, montelukast, andpioglitazone. A fold increase of 1 refers to no effect of inhibitors on drugexposure. References are given in Table 10 and in the text.

Fig. 9. Predicted effects of different gemfibrozil doses on CYP2C8-mediated drug metabolism. Predicted fold increase in the AUC0–‘ of adrug metabolized by CYP2C8, when the fraction of the substrate drugmetabolized by CYP2C8 (fm,CYP2C8) varies between 50 and 99% (A),and the CYP2C8 activity remaining (B) after a gemfibrozil dose rangingfrom 0 to 600 mg twice daily in steady-state conditions. Modified fromHonkalammi et al. (2012). AUC, area under the concentration-time curve.

218 Backman et al.

http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2015/54454a-eng.php

http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2015/54454a-eng.php

by CYP2C8 and to lesser extent by CYP3A4, whereasCYP2C9 is not significantly involved in pioglitazoneelimination. In healthy volunteers, gemfibrozil raisedthe mean AUC of pioglitazone 3.2-fold (range 2.3-foldto 6.5-fold) and its elimination half-life 2.7-fold, butitraconazole had no effect on pioglitazone and did notalter the effect of gemfibrozil on its pharmacokinetics(Jaakkola et al., 2005). In two other studies, gemfibrozilincreased the mean AUC of pioglitazone 3.4-fold (Denget al., 2005) and 4.3-fold (range 1.3-fold to 12.1-fold)(Aquilante et al., 2013a). CYP2C8 genotype influencesthe relative change in pioglitazone exposure aftergemfibrozil administration. Thus, CYP2C8*3 carriershad a greater mean increase by gemfibrozil in pioglita-zone AUC (5.2-fold) compared with CYP2C8*1 homozy-gotes (3.3-fold) (Aquilante et al., 2013a). Trimethoprim(160 mg twice daily) raised in healthy volunteers theAUC of pioglitazone by 1.4-fold and had opposite effectson pioglitazone pharmacokinetics compared with theeffects of CYP2C8*3 allele during the placebo phase(Tornio et al., 2008b).The AUC of rosiglitazone was raised in healthy

volunteers by gemfibrozil by 2.3-fold (Niemi et al.,2003a). In another study, trimethoprim (160 mg twicedaily) increased rosiglitazone AUC by 1.4-fold and re-duced the formation ofN-demethylrosiglitazone (Niemiet al., 2004a). The effect of trimethoprim (200 mg twicedaily) on rosiglitazone pharmacokinetics was confirmedby Hruska et al. (2005), who also demonstrated thecompetitive inhibition of rosiglitazone p-hydroxylationby trimethoprim in vitro. Atazanavir (400 mg once daily)increased the AUC of a single dose of rosiglitazone by1.4-fold (FDA, 2015b).The AUC of nateglinide was increased only by 1.5-fold

by 3 days’ pretreatment with therapeutic doses of bothgemfibrozil and itraconazole (Niemi et al., 2005a). Thus,neither CYP2C8 nor CYP3A4 has a substantial signif-icance to the pharmacokinetics of nateglinide. Gem-fibrozil increased also the AUC of the dipeptidylpeptidase inhibitor sitagliptin by 1.5-fold (Arun et al.,2012). However, the gemfibrozil-sitagliptin interactionseems to be mainly mediated by inhibition of the renalOAT3, with a minor contribution by CYP2C8.If gemfibrozil, clopidogrel, or other inhibitors of

CYP2C8 will be combined with pioglitazone or rosiglita-zone, blood glucose levels, symptoms of hypoglycemia, andother potential adverse effects (e.g., fluid retention) shouldbe monitored closely and the doses be modified as needed.As shown for the gemfibrozil-pioglitazone and gemfibrozil-repaglinide interactions (Tornio et al., 2008a; Aquilanteet al., 2013a), interactions may be stronger in CYP2C8*3carriers than in CYP2C8*1 homozygotes.3. Amodiaquine. Although amodiaquineN-deethylation

is a widely used marker reaction for CYP2C8 activityin vitro, the sensitivity of amodiaquine to CYP2C8inhibition is poorly characterized in humans. Amodia-quine is rapidly and extensively metabolized by

CYP2C8 to active desethylamodiaquine, which has along half-life of 9–18 days. In healthy subjects, tri-methoprim and efavirenz have been reported to in-crease the AUC of amodiaquine by 1.6- and 1.8-fold,respectively, and to reduce that of desethylamodiaquineby 12 and 26%, respectively (Soyinka et al., 2013;Akande et al., 2015). In an earlier study, efavirenzraised the AUC of amodiaquine in two healthy subjectsby 2- to 4-fold and decreased the AUC of desethylamo-diaquine by 24 and 8.5% (German et al., 2007). In both ofthese subjects, marked elevation of hepatic transami-nase levels occurred several weeks after stopping the 3days’ combined use, forcing premature discontinuationof the interaction study. The dramatic, delayed hepato-toxicity warrants great care in combination of anyCYP2C8 inhibitor with amodiaquine.

4. Statins. Cerivastatin was initially considered as asafe statin because of its dual biotransformation routes,mediated both via CYP3A4 and CYP2C8 (Mück, 1998;2000). However, it soon became obvious that cerivasta-tin greatly increased the incidence of fatal rhabdomyol-ysis, particularly when taken along with gemfibrozil(Staffa et al., 2002). Consequently, cerivastatin waswithdrawn from the market in 2001, only 3 years afterits launch. Despite the “dual metabolic pathway” andsupposed "low propensity for drug interactions" (Mücket al., 1998; Mück, 2000), the elimination of cerivastatinrelied predominantly on CYP2C8. In healthy volun-teers, gemfibrozil (600 mg twice daily) raised the AUCof the parent cerivastatin (acid) by 5.6-fold, the AUCof cerivastatin lactone by 4.4-fold, and that of theCYP3A4-dependent metabolite M-1 by 4.35-fold,whereas gemfibrozil decreased the AUC of theCYP2C8-dependent metabolite M-23 by 78% (Fig. 11;Backman et al., 2002). The increased exposure tocerivastatin, to its lactone, and to M-1 and the reducedformation of the CYP2C8-dependent metabolite re-vealed the strong CYP2C8 inhibitory effect of gemfi-brozil. In addition to irreversible inhibition of CYP2C8by gemfibrozil 1-O-b-glucuronide, inhibition of thehepatic OATP1B1 may contribute to the gemfibrozil-cerivastatin interaction (Ogilvie et al., 2006; Shitaraet al., 2004; Tamraz et al., 2013).

Interestingly, about 10 years after the withdrawal ofcerivastatin, it was found that in addition to gemfibro-zil, also concomitant use of clopidogrel was stronglyassociated with cerivastatin-induced rhabdomyolysis,with an odds ratio of ;30 (48 when gemfibrozil userswere excluded) (Floyd et al., 2012). Recently, Tornioet al. (2014) showed that glucuronidation convertsclopidogrel to a strong time-dependent inhibitor ofCYP2C8, clopidogrel acyl-b-D-glucuronide. The forma-tion of this metabolite leads to uninterrupted inhibitionof CYP2C8 during clopidogrel treatment and explainsthe increased risk of rhabdomyolysis during concomi-tant use of cerivastatin and clopidogrel (Tornio et al.,2014). Also trimethoprim increased the AUC of


cerivastatin (by 1.4-fold) and its lactone (1.5-fold)(Backman et al., 2003). Because cerivastatin has beenwithdrawn from the market, its interactions are nomore of direct clinical relevance. However, they areexamples of clinically important challenges in drugdevelopment and have been of paramount importancein understanding the significance of CYP2C8 in drugmetabolism.Interestingly, cerivastatin and repaglinide have

pharmacokinetic similarities. Both drugs are sub-strates of CYP2C8, CYP3A4, and OATP1B1. TheCYP3A4 inhibitor itraconazole has raised their AUConly slightly, i.e., by 1.4-fold (repaglinide), 1.15-fold(cerivastatin acid), and 1.8-fold (cerivastatin lactone),whereas gemfibrozil has raised their AUC values muchmore, i.e., by 8.1-fold (repaglinide), by 5.6-fold (cerivas-tatin), and by 4.4-fold (cerivastatin lactone) (Kantolaet al., 1999; Backman et al., 2002; Niemi et al., 2003b).Because the combination of a CYP3A4 inhibitor and aCYP2C8 inhibitor caused a drastic increase in repagli-nide AUC (by 19.4-fold; Niemi et al., 2003b), it isreasonable to assume that also the exposure to cerivas-tatin acid and to its more lipophilic lactone form haveraised even more by gemfibrozil—or clopidogrel—if thepatients had been using also CYP3A4 inhibiting drugs.However, there seems to be no studies on the effect ofCYP2C8 and CYP3A4 inhibitor combinations on theplasma concentrations of cerivastatin.

Gemfibrozil raises the AUC of nearly all statin acids,including simvastatin acid, lovastatin acid, atorva-statin, pravastatin, rosuvastatin, and pitavastatin(Neuvonen et al., 2006). However, the role of CYP2C8 insome gemfibrozil-statin interactions seems to be limited ornonexistent. They are mainly mediated by inhibitionof OATP1B1, OAT3, or other transporters (Shitaraet al., 2004; Neuvonen, 2010; Niemi et al., 2011).

5. Anticancer Drugs. Most anticancer drugs have anarrow therapeutic range. Although paclitaxel is a well-established CYP2C8 probe in vitro, its interactions withCYP2C8 inhibitors and inducers have not been widelystudied in humans. Lapatinib and pazopanib are rela-tively strong inhibitors of CYP2C8, and they haveraised the AUC of paclitaxel up to 1.8-fold (Tan et al.,2014). In a case report, the only clopidogrel user in acohort of 93 ovarian carcinoma patients treated withpaclitaxel had the second lowest clearance of unboundpaclitaxel in the cohort. She was hospitalized threetimes because of severe paclitaxel toxicity (Bergmannet al., 2015).

Gemfibrozil has raised the AUC of the androgenreceptor antagonist enzalutamide by 4.3-fold, and itra-conazole raised it by 1.4-fold compared with control(Gibbons et al., 2015). These results agree well with the invitro findings that CYP2C8 is the predominant enzyme inthe elimination of enzalutamide. The composite exposureof enzalutamide and its active metabolite was raised by

Fig. 11. Effects of gemfibrozil on the plasma concentrations of cerivastatin, its lactone, and M-1 and M-23 metabolites after administration ofcerivastatin 0.3 mg with gemfibrozil 600 mg or placebo twice daily for 3 days (modified from Backman et al., 2002).

220 Backman et al.

2.2-fold by gemfibrozil and by 1.3-fold by itraconazole. Areduction of the enzalutamide dose by about 50% isrecommended when gemfibrozil is used concomitantly.There are no published studies on the effect of clopidogrelon enzalutamide pharmacokinetics. However, a closefollow up and reduction of enzalutamide dose can berecommended also in their possible coadministration. Itshould also be noted that combined inhibition ofCYP2C8 and CYP3A4 can cause a greater increase inenzalutamide + metabolite AUC. Enzalutamide itself isan inhibitor of CYP2C8 and may moderately raise theexposure to its substrate drugs, e.g., pioglitazone AUCby 20% (Gibbons et al., 2015).Gemfibrozil did not affect the AUC of imatinib

after a single imatinib dose but reduced the AUC ofN-demethylimatinib by 48%, indicating a significantparticipation of CYP2C8 in themetabolism of imatinib inhumans (Filppula et al., 2013b). After a single dose,imatinib seems to be mainly metabolized by CYP3A4,but the fraction of imatinib metabolized by CYP3A4decreases after its multiple doses because of auto-inhibition of the CYP3A4-mediated metabolism ofimatinib (Filppula et al., 2012, 2013a). This autoinhibi-tion is likely to increase the relative role of CYP2C8in imatinib elimination and its sensitivity to interac-tions caused by CYP2C8 inhibitors during long-termtreatment. According to pharmacokinetic simulations,imatinib exposure may raise up to twofold at steady stateif a strong CYP2C8 inhibitor is given concomitantly withimatinib (Filppula et al., 2013b).In melanoma patients, gemfibrozil increased the

AUC of the CYP3A4 and CYP2C8 substrate dabrafenibby 1.5-fold and ketoconazole increased it by 1.7-fold(Suttle et al., 2015). It is probable that a combinedadministration of CYP2C8 inhibitors and CYP3A4inhibitors with dabrafenib can increase its exposuremore than does either of these inhibitors alone. Inaddition to paclitaxel, dabrafenib, and imatinib, someother anticancer drugs are metabolized by CYP2C8(Table 1). However, their interactions with CYP2C8inhibitors have not been characterized in humans.Considering the narrow therapeutic range of manyanticancer drugs, close follow up for possible adverseeffects is warranted if gemfibrozil, clopidogrel, trimeth-oprim, or other inhibitors of CYP2C8 are used with pacli-taxel or other anticancer drugs metabolized by CYP2C8.6. Antiviral Drugs. Gemfibrozil (600 mg twice daily)

has increased the AUC of the antihepatitis C drugdasabuvir about 11-fold and their concomitant use iscontraindicated (Menon et al., 2015). It is reasonable toassume that also other potent inhibitors of CYP2C8such as clopidogrel increase greatly the exposure todasabuvir, and their use together should be avoided orthe dose of dasabuvir be reduced markedly. It can bespeculated that savings could be achieved by usingsmall amounts of expensive dasabuvir (about one-tenthof normal dose) with small doses (e.g., 100 mg) of

gemfibrozil. This should lead to similar plasma concen-trations of dasabuvir as those achieved by normaldasabuvir doses administered without inhibitor ofCYP2C8. Also some other new antiviral drugs arepartially metabolized by CYP2C8, but their suscepti-bility to interact with drugs affecting CYP2C8 activityin humans needs further studies.

7. Antiasthmatic Drugs. In healthy volunteers.gemfibrozil raised the AUC of montelukast 4.5-foldand its elimination half-life 3.0-fold (Karonen et al.,2010). Gemfibrozil reduced the AUC of the secondaryM4 metabolite of montelukast by more than 90%. Inanother study, gemfibrozil alone raised the AUC ofmontelukast 4.3-fold, itraconazole had no significanteffects, and the effects of the gemfibrozil-itraconazolecombination on montelukast pharmacokinetics did notdiffer from those of gemfibrozil alone (Karonen et al., 2012).These findings indicate that CYP2C8 but not CYP3A4 isimportant in the pharmacokinetics of montelukast. Incontrast to the effect of gemfibrozil on montelukast, thepharmacokinetics of zafirlukast is not affected by gemfi-brozil (Karonen et al., 2011), although both of thesecysteinyl leukotriene receptor antagonists are potent invitro inhibitors of CYP2C8 (Walsky et al., 2005a).

Montelukast has a relatively large safety margin, andthe clinical significance of its interactions with CYP2C8inhibitors seems to be limited. However, neuropsychi-atric symptoms have developed in a woman with HIVinfection when montelukast was added to her therapycontaining the CYP2C8 inhibitor efavirenz (Ibarra-Barrueta et al., 2014). She had used efavirenz, emtrici-tabine, and tenofovir disoproxil fumarate for yearswith good tolerance until montelukast was startedfor asthma. Shortly thereafter unbearable symptomsappeared, consisting of disturbed sleep, vivid dreamsand irritability, confusion, and concentration difficulties.After 2 months of concomitant use, montelukast waswithdrawn and the psychiatric symptoms completely dis-appeared. This case report indicates that adverse effectscan develop when these drugs are used together, althoughthe mechanism of adverse effects is not fully clear.

8. Other Substrate or Inhibitor Drugs. Gemfibrozilraised in healthy volunteers the AUC of loperamide2.1-fold, itraconazole raised it 3.8-fold, and thegemfibrozil-itraconazole combination raised lopera-mide AUC 12.6-fold compared with placebo phase(Niemi et al., 2006). This finding strongly suggeststhat gemfibrozil can markedly increase the loperamideexposure in subjects who are using potent inhibitorsof CYP3A4, i.e., when another important metabolicroute is blocked. Administration of cotrimoxazole(trimethoprim + sulphamethoxazole) has increased theAUC of loperamide by 1.9-fold (Kamali and Huang,1996). Also some other opioids, e.g., buprenorphine, areCYP2C8 substrates (Table 1). However, there seem to beno published studies on their possible interaction withgemfibrozil or other CYP2C8 inhibitors.


Gemfibrozil raised the AUC of the prolyl hydroxylaseinhibitor agent daprodustat (GSK1278863) 18.6-fold(Johnson et al., 2014). This result together with in vitrostudies indicates the crucial significance of CYP2C8 inits pharmacokinetics. CYP2C8 inhibitors should not beused with this erythropoiesis-stimulant agent or its doseneeds to be reduced very greatly. On the other hand, atleast theoretically, it could be possible to take advantage ofthis interaction in a product containing very small doses ofdaprodustat and gemfibrozil.In healthy volunteers, gemfibrozil raised only slightly

the AUC of R-ibuprofen, by 1.3-fold, after the ingestionof racemic ibuprofen (Tornio et al., 2007). In vitroCYP2C8 participates in the metabolism of zopiclone(Becquemont et al., 1999). In humans, however, gemfi-brozil did not increase the AUC of the parent zopiclonebut moderately (2-fold and 1.2-fold) increased the AUCof its potentially active metabolites (Tornio et al., 2006).Also many other drugs are substrates of CYP2C8 invitro, but their concomitant administration with gemfi-brozil hasnot appreciably increased theirAUC, suggestingthat the CYP2C8-mediated biotransformation is of lim-ited significance to their total clearance (Table 1).Many compounds are moderate inhibitors of CYP2C8

in vitro, but their concomitant ingestion with repagli-nide or other CYP2C8 substrates does not raise expo-sure to these substrates in humans. The reason for theapparent discrepancy between the in vitro and in vivoresults can be, for example, their low potency asCYP2C8 inhibitors or their high protein binding in vivo(e.g., montelukast).Some parent drugs such as gemfibrozil and clopidog-

rel are relatively weak inhibitors of CYP2C8 in vitro,but they are metabolized in vivo to glucuronide metab-olites, which are potent CYP2C8 inhibitors. In general,negative interaction results with gemfibrozil in vivoexclude a clinically meaningful interaction mediatedby CYP2C8 inhibition. On the other hand, increasedexposure to a victim drug by gemfibrozil does not yetindicate that CYP2C8 has a significant role in itsmetabolism because there may be other mechanismsmediating the observed interaction.Patients often concomitantly use different drugs

that together inhibit several CYP enzymes, e.g.,CYP1A2, CYP2C8, CYP2C9, CYP2B6, CYP2D6, orCYP3A4. The combined inhibition of two or more ofthese enzymes often results in patients in a strongerinteraction than is caused by inhibition of a singleenzyme in healthy volunteer studies. This aspecttogether with other causes of interindividual variationshould be taken into consideration when the results ofexperimental interaction studies in healthy volunteersare translated into the clinic.

D. Induction-Mediated Drug Interactions

Rifampin (rifampicin) can markedly increase theclearance of many CYP2C8 substrate drugs, decrease

their AUC, and diminish their clinical efficacy. BothCYP2C8 and CYP3A4 are involved in the biotransfor-mation of many drugs, which can also be substrates ofvarious transporters (Table 1). Because both CYP2C8 andCYP3A4 enzymes and some transporters can be highlyinducible, the importance of CYP2C8 in many rifampininteractions is difficult to determine exactly (Niemi et al.,2000). Apart from rifampin, there are very few clinicalstudies concerning the effects of other CYP enzymeinducers on the pharmacokinetics of CYP2C8 substrates.

1. Rifampin (Rifampicin). Rifampin (600 mg/day),given for several days, has decreased the plasmaexposure to repaglinide by 31–80% depending on thetime interval from the last rifampin dose to repaglinideingestion (Table 11; Niemi et al., 2000; Hatorp et al.,2003; Bidstrup et al., 2004). The time interval affectsthe extent of interaction because rifampin is alsoa competitive inhibitor of OATP1B1, CYP2C8 andCYP3A4 (Kajosaari et al., 2005a; Varma et al., 2013).Interestingly, intake of St John’s Wort for 14 days hashad no significant effect of the pharmacokinetics ofrepaglinide (Fan et al., 2011).

Rifampin has also reduced the concentrations of thethiazolidinediones pioglitazone and rosiglitazone. Ri-fampin caused a substantial (54%) decrease in the AUCof pioglitazone and increased the ratios of metaboliteM-IV to pioglitazone and of M-III to pioglitazone in urineby 98 and 95% (Jaakkola et al., 2006a). Similarly,rifampin reduced the mean AUC of rosiglitazone by54% and increased the formation of N-demethylrosigli-tazone (Niemi et al., 2004a). In Korean men, rifampindecreased rosiglitazone AUC by 65% (Park et al., 2004).Addition of tuberculosis treatment, containing rifam-pin, to treatment of a woman with type 2 diabetescaused her to lose glycemic control, demonstrating poten-tial clinical significance of the rifampin-rosiglitazoneinteraction (Pimazoni, 2009).

VII. Points to Consider When InvestigatingCytochrome P450 2C8-Mediated Drug

Metabolism and Interactions

Studies focusing on drug metabolism and metabolicdrug-drug interactions are an essential part of moderndrug development, from early preclinical phases tothe clinical development phase and beyond. By usingspecific and sensitive research methods, it is possibleto get a detailed and accurate view of potential issuesrelated to variability in drugmetabolism already duringthe preclinical and early clinical phases of development.Methods to investigate CYP2C8 in vitro and in clinicalstudies have evolved markedly even during the lastdecade.

A. In Vitro

1. General Aspects. Comprehensive in vitro studiesto investigate the roles of different CYP enzymes in the

222 Backman et al.

metabolism of a (new) drug and to uncover its potentialfor causing inhibition or induction of drug metabolismare typically conducted already during the early pre-clinical phases of drug development. The results fromthese studies are then used for in vitro-in vivo extra-polations, to anticipate factors affecting the clearanceof the drug as well as its potential to act as a perpetratorof pharmacokinetic drug interactions, i.e., to affect theclearance of other drugs. The prerequisite for accurateextrapolations is that in vitro investigations are con-ducted with care and are sufficiently comprehensive,avoiding the many pitfalls of in vitro studies, under-standing the many limitations of the different ap-proaches, and covering complex issues, such as thepotential for autoinhibition or -induction. Yet it shouldbe understood that accurate extrapolations are notpossible without some clinical pharmacokinetic dataat the relevant dose of the investigational drug.The general aspects as well as the potential pitfalls of

in vitro studies and extrapolations are well covered bymanyexcellent review articles and guidelines (Houston andGaletin, 2008; Pelkonen et al., 2008; Grimm et al., 2009;EMA, 2012b; Pelkonen, 2015; http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm). Therefore,this review focuses on issues that are directly relatedto CYP2C8, i.e., in vitro methods used for measurementof CYP2C8 activity (e.g., to test the potential of theinvestigational drug to inhibit CYP2C8 activity) andreaction phenotyping (does CYP2C8 metabolize thedrug) and in vivo studies to characterize the druginteraction potential of the new drug (either as aperpetrator or victim drug).2. Assessment of CYP2C8 Activity In Vitro.

Specific assessment of CYP2C8 activity is necessary, inparticular when studying the potential of a drug to causeinhibition of CYP2C8 but alsowhenusing a panel ofHLMfor reaction phenotyping using the correlation approach.An ideal in vitro probe substrate is selective/specific, hasa sufficient turnover, follows Michaelis-Menten kinetics,and is not sensitive to experimental conditions. There areseveral useful, selective probe substrates to studyCYP2C8 in vitro, including paclitaxel, amodiaquine,

montelukast, rosiglitazone, pioglitazone, and cerivasta-tin, each having its specific strengths and weaknesses(Tables 12 and 13).

Paclitaxel 6-a-hydroxylation is the prototypicalmarker reaction for CYP2C8 (Rahman et al., 1994;Sonnichsen et al., 1995). It is highly selective forCYP2C8, but the metabolic turnover is fairly low, oftenleading to relatively long incubation times, which maylead to significant inhibitor metabolism/depletion dur-ing the incubation (Table 13). This may partly explainwhy paclitaxel seems to be less sensitive to competitiveCYP2C8 inhibitors than most other CYP2C8 markersubstrates (VandenBrink et al., 2011). In particular,long incubation times should be avoided when studyingthe potential for time-dependent or mechanism-basedinhibition in systems based on a preincubation step,because inactivation proceeding during the incubationmay decrease the sensitivity of the experimental systemto detect inactivation.

Amodiaquine metabolism to N-desethylamodiaquineis probably the second most used CYP2C8 markerreaction. It is well characterized and highly selectivefor CYP2C8 and has a high turnover (Li et al., 2002),allowing for short incubation times. Overall, it seems tohave no major drawbacks in in vitro use.

Few years ago, montelukast, a selective competitiveinhibitor of CYP2C8, was shown to be a potentialCYP2C8 marker substrate, because its 36-hydroxylation(M6 formation) is mediated primarily by CYP2C8 witha minor contribution by CYP2C9 (Filppula et al., 2011).In a successive study, montelukast 36-hydroxylationproved to be a sensitive and useful reaction to in-vestigate CYP2C8 inhibition in vitro (VandenBrinket al., 2011). One of the weaknesses of montelukastis that it is highly susceptible to microsomal proteinbinding, necessitating careful standardization of incuba-tion conditions (Walsky et al., 2005b).

Of the other potential marker reactions, cerivastatin6-hydroxylation (M-23 formation) seems to be highlyspecific for CYP2C8 (Wang et al., 2002; Shitara et al.,2004). In addition, the hydroxylations of rosiglitazone(p-hydroxylation) (Baldwin et al., 1999) and pioglita-zone (M-IV formation; Jaakkola et al., 2006c) seem to be

TABLE 11Drug-drug interactions caused by the CYP2C8-inducing drug rifampin (rifampicin) in humans

Inducer DosingTime Interval from the

Previous Rifampin Dose toSubstrate Ingestion

Substrate AUC Decrease References

hours %

600 mg once daily for 6 days 13 Pioglitazone 54 Jaakkola et al., 2006a- Active metabolite: ketopioglitazone (M-III) 39 Jaakkola et al., 2006a- Active metabolite: hydroxypioglitazone (M-IV) 34 Jaakkola et al., 2006a

600 mg once daily for 5 days 12.5 Repaglinide 57 Niemi et al., 2000600 mg once daily for 7 days 1 31 Hatorp et al., 2003600 mg once daily for 7 days 0 48 Bidstrup et al., 2004

24 80 Bidstrup et al., 2004600 mg once daily for 5 days 13 Rosiglitazone 54 Niemi et al., 2004a600 mg once daily for 6 days 12 65 Park et al., 2004

AUC, area under the plasma concentration-time curve.





relatively, albeit not completely, selective for CYP2C8.Finally, the most used in vivo CYP2C8 probe drugrepaglinide, although sometimes recommended as an invitro probe (Kajosaari et al., 2005a; VandenBrink et al.,2011), is challenging to use in vitro, e.g., because of aneed for extremely low substrate concentrations andlack of commercially available metabolite standards(Table 13).3. In Vitro Methods to Estimate the Contribution

of CYP2C8 in the Metabolism of a Drug. The basicmethods used for estimating the contributions of CYPenzymes to the metabolism of a drug, i.e., the so-calledreaction phenotyping, are the use of diagnostic inhibi-tors in a complete natural system, such asHLM, and theuse of recombinant expressed enzymes. In both ap-proaches, knowledge of clinically relevant concentra-tions of the drug is a prerequisite for estimation of thecontributions of the different CYP enzymes in vivo. Theadvantage of HLM is the natural composition of thesystem, allowing relatively straightforward estimationof the contributions. However, this approach requireshuman material collected according to high ethicalstandards and is entirely dependent on the strengthand specificity of the inhibitors. On the other hand,although recombinant expressed enzymes can beregarded as a specific tool, in vivo extrapolations ofrecombinant enzyme results require the use of en-zyme source and batch specific conversion factors(preferably based on enzyme activity), complicatingthe extrapolations.Recombinant expressed human CYP2C8 is commer-

cially available at least as bacterial cell- and insect cell-based products. During the last decade, both chemicalinhibitors and inhibitory antibodies have become avail-able that are both CYP2C8 specific and strong. In thefollowing, we review the documentation regardingchemical CYP2C8 inhibitors.

One of the most widely used chemical CYP2C8inhibitors is quercetin (Rahman et al., 1994). However,it is neither very selective for CYP2C8 nor very strongand therefore, it can barely be recommended as adiagnostic inhibitor. Today, there are several moreselective alternatives available, including trimetho-prim, montelukast, and gemfibrozil 1-O-b-glucuronide.

The IC50 of trimethoprim for CYP2C8 is approxi-mately 50 mM, i.e., it is not a very strong inhibitor, butits IC50 for other CYP enzymes is at least one order ofmagnitude greater, making it a relatively selectiveinhibitor (Wen et al., 2002). Montelukast, on the otherhand, is a potent and highly selective competitiveinhibitor of CYP2C8, with an IC50 as low as 0.01 mM,when a low microsomal protein concentration is used,whereas its IC50 for other CYP enzymes is at least twoorders of magnitude greater (Walsky et al., 2005b). Themajor drawback of montelukast seems to be its non-specific microsomal protein binding, whereby increas-ing the microsomal protein concentration by 80-foldyields an about 100-fold decrease in its inhibitionpotency (Walsky et al., 2005b).

Themechanism-basedCYP2C8 inactivator gemfibrozil1-O-b-glucuronide is another appealing CYP2C8 inhibi-tor.With a 30-minute preincubation, its IC50 for CYP2C8is about 2 mM, whereas its IC50 values for CYP1A2,CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 aremore than 300 mM, suggesting an even better selectivitythan that of montelukast (Ogilvie et al., 2006). Moreover,it is unlikely to be markedly affected by microsomalprotein concentration. Whether clopidogrel acyl-b-D-glucuronide is a similarly selective CYP2C8 inactivatorremains to be investigated (Tornio et al., 2014).

B. In Vivo

1. General Aspects. Current guidelines recommendthe conduct of clinical drug-drug interaction studies on

TABLE 12CYP2C8 substrate, inhibitor, and inducer probes recommended for drug-drug interaction studies

Probe EMAa FDAb Helsinki DDI Group

In Vitro In Vivo In Vitro In Vivo In Vitro In Vivo

Substrate Paclitaxel Amodiaquine Paclitaxelc Repaglinide Amodiaquine RepaglinideAmodiaquine Repaglinide Amodiaquine Rosiglitazone Paclitaxel Montelukast

Rosiglitazone Montelukast PioglitazoneCerivastatin (acid) Rosiglitazone(Pioglitazone) (Dasabuvir)

Inhibitor Montelukast Gemfibrozil Montelukastc Gemfibrozil Montelukast GemfibrozilQuercetinc Gemfibrozil

1-O-b glucuronideClopidogrel

Trimethoprim Clopidogrel acyl1-b-D-glucuronide

(Trimethoprim)

Gemfibrozil (Trimethoprim)RosiglitazonePioglitazone

Inducer None recommended None recommended Rifampin (rifampicin) Rifampin (rifampicin) Rifampin (rifampicin) Rifampin(rifampicin)

DDI, drug-drug interaction; EMA, European Medicines Agency; FDA, Food and Drug Administration.aEMA, 2012b.bhttp://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm (Accessed September 15, 2015).cPreferred.

224 Backman et al.


the basis of in vitro studies on the CYP inhibitoryeffects of the drug and its main circulatingmetabolites(potential perpetrator), as well as on the basis of theresults of the in vitro reaction phenotyping studies ofthe drug and its main metabolic pathways (victim). Arational selection for the first CYP-specific clinicalstudies is to focus on the enzyme that is inhibited most(lowest IC50/Ki) by the drug or its metabolite, prefer-ably using the highest clinically used dose of the drug,and on the enzyme that is considered the mostimportant in its own metabolism. For the first typeof studies, a sensitive and selective in vivo probesubstrate is used, and for the second type of studies,a strong and selective in vivo probe inhibitor is needed.For CYP2C8, there are several alternative probesubstrates and a few inhibitors that can be used inclinical trials.

The contribution of CYP2C8 enzyme to the totalclearance of its substrates varies greatly (Table 1).Most CYP2C8 substrates are partially metabolized alsoby other enzymes, are substrates of some membranetransporters, or are excreted in urine or feces in un-changed form. Thus, the significance of CYP2C8 ininteractions cannot be calculated directly from changesin victim drug AUC. If the CYP2C8 substrate drugis also a substrate of transporters or other CYPenzymes, their contribution needs to be considered inthe interaction, as exemplified in the dissection ofthe gemfibrozil-repaglinide interaction (Honkalammiet al., 2011a, 2012). For example, gemfibrozil is in vivoan inhibitor of CYP2C8 as well as of OATP1B1 andOAT3, and it can increase the AUC of certain drugs(e.g., pravastatin), which are not substrates of CYP2C8but are substrates for OATP1B1 or OAT3 (Kyrklundet al., 2003). On the other hand, CYP2C8 inhibitorsusually increase the AUC of CYP2C8 substrates lessthan they diminish the CYP2C8-specific metabolicroutes, because the CYP2C8-independent eliminationroutes remain unaffected.

CYP2C8-mediated drug interactions are often stud-ied in healthy volunteers in a randomized crossovermanner by administering a potential substrate drugwith and without a probe inhibitors of CYP2C8, suchas the recommended probe inhibitor gemfibrozil(Table 12). To better simulate real clinical situationsin which patients often are using several different drugsconcomitantly, substrate drugs can be administered inmultiple-phase studies, given alone, with an inhibitor ofCYP2C8 (gemfibrozil), with an inhibitor of anotherrelevant CYP enzyme (e.g., with CYP3A4 inhibitoritraconazole), and together with a combination ofinhibitors. However, there are only a few studies inwhich the effects of multiple inhibitors (e.g., inhibitorsof CYP2C8 and CYP3A4) on the pharmacokinetics oftheir substrate drugs have been studied both separatelyand together (Niemi et al., 2003b, 2006; Jaakkola et al.,2005; Karonen et al., 2012).

TABLE

13Stren

gths

andwea

knessesof

therecommen

dedpr

obecompo

unds

InVitro

InVivo

Probe

Stren

gths

Wea

knesses

Probe

Stren

gths

Wea

knesses

Subs

trate

Amod

iaqu

ine

Selectivity,high

turn

over

Rep

aglinide

Sen

sitivity,sh

ortha

lf-life

Red

uces

bloodgluc

oseleve

ls,

also

asu

bstrateof

OATP1B

1an

dCYP3A

4Pac

litaxel

Selectivity,ex

tens

ive

docu

men

tation

Low

/interm

ediate

turn

over,

solubility

issu

esMon

teluka

stRelativesens

itivity,

safety

Med

ium

long

half-life

Mon

teluka

stSelectivity

Con

tributionby

CYP2C

9,requ

irem

ent

forve

rylow

subs

trateconc

entration,

issu

eswithpr

oteinbind

ing

Pioglitaz

one

Relativesens

itivity,

safety,no

ta

subs

trateof

OATP1B

1Lon

gha

lf-life

Cerivas

tatin(acid)

Selectivity

Ava

ilab

ilityof

referenc

ecompo

unds

Rep

aglinide

Selectivity

Lackof

metab

olitestan

dard

s,contribu

tion

byCYP3A

4,requ

irem

entforlow

subs

trate

conc

entration

Rosiglitazone

Safety,

not

asu

bstrateof

OATP1B

1Onlymod

eratesens

itivity,

long

half-life,

notea

sily

available

inallcoun

tries

Pioglitaz

one

Selectivity

Low

/interm

ediate

turn

over

Das

abuvir

Sen

sitive

Lackof

docu

men

tation

Rosiglitazone

Selectivity

Low

/interm

ediate

turn

over

Inhibitor

Gem

fibrozil1-O-b

glucu

ronide

Poten

cySelectivity

notwelldo

cumen

ted,

requ

ires

apr

einc

ubation

Gem

fibrozil

Stren

gth,

selectivity

Mod

erateinhibitorof

OATP1B

1an

dOAT3

Clopidog

relac

yl1-b-D

-glucu

ronide

Selectivity

notdo

cumen

ted,

requ

ires

apr

einc

ubation

Clopidog

rel

Stren

gth,

not

aninhibitorof

OATP1B

1or

CYP3A

4AlsoCYP2B

6inhibitor

Mon

teluka

stPoten

cy,selectivity

Alsoasu

bstrateof

CYP2C

8,microsomal

proteinbind

ing

Trimethop

rim

Selectivity

Wea

kinhibitor

Indu

cer

Rifam

pin

(Rifam

picin)

Poten

cy,well-do

cumen

ted

indu

cer

Non

selective

Rifam

pin

(Rifam

picin)

Stron

g,well-do

cumen

tedindu

cer

Non

selective


2. In Vivo Cytochrome P450 2C8 Probe Substrates.The crucial characteristics of an in vivo probe substrateare its selectivity and sensitivity. In an ideal case, atleast 80% of the substrate is metabolized by the enzymeof interest, allowing for an interpretation based on theAUC of the parent drug. In some cases, the use of anenzyme-specific metabolite to parent ratio may beused to increase sensitivity and specificity, but withan additional caveat because of potential variability inmetabolite elimination. The feasibility of an in vivoprobe substrate also depends heavily on its safety, inparticular when large increases in its systemic concen-trations can be anticipated. Moreover, the pharma-cokinetic characteristics of the probe may affect itssuitability. For example, a probe substrate with asignificant first-pass metabolism and short eliminationhalf-life may be able to catch even transient changes inenzyme activity, which may be necessary when study-ing inhibitors with a short half-life or time-dependentchanges in enzyme activity.The antidiabetic agent repaglinide is overall the most

studied and best documented in vivo probe substrate ofCYP2C8, and consequently both the European Medi-cines Agency (EMA) and FDA recommend its use as aCYP2C8 probe (Table 12). Although in vitro studiesare not fully consistent with the major in vivo role ofCYP2C8 in the total metabolism of repaglinide (Ganet al., 2010; Säll et al., 2012; Varma et al., 2013, 2015),repaglinide seems to be very sensitive to inhibitors ofCYP2C8 activity, such as gemfibrozil, trimethoprim,and clopidogrel (Niemi et al., 2003b, 2004b; Tornio et al.,2014). On the basis of detailed mechanistic drug-druginteraction studies with the strong CYP2C8 inactivatorgemfibrozil, it has been estimated that the contributionof CYP2C8 to repaglinide (0.25 mg) metabolism is about85%, indicating that the AUC of repaglinide can beincreased up to an average of sevenfold by strongCYP2C8 inhibition (Honkalammi et al., 2012). Thehalf-life of repaglinide is also relatively short (1 hour),which allows for a full pharmacokinetic study within 1day and can be beneficial when a measure of CYP2C8activity within a narrow time frame is desired. Theweakness of repaglinide is that it is partially metabo-lized by CYP3A4 (Bidstrup et al., 2003; Niemi et al.,2003b; Kajosaari, 2005a) and also a substrate ofOATP1B1 (Niemi et al., 2005b). Thus, e.g., the effect ofgemfibrozil on repaglinide pharmacokinetics is par-tially mediated by inhibition of OATP1B1, in additionto inhibition of CYP2C8 (Honkalammi et al., 2011a).Moreover, as it increases insulin secretion from pancre-atic b cells, there is a risk of hypoglycemia, particularlywhen it is given to healthy subjects. Thus, the smallestpossible dose (e.g., 0.25 mg) of repaglinide should beused, and meals, close follow up, and blood glucosemonitoring be arranged when repaglinide is used.Theoretically, the antimalarial agent amodiaquine and

itsN-deethylation could be useful in vivo CYP2C8 probes.

However, there is very little clinical documentation for itsuse as a probe drug. Moreover, the safety of amodiaquineas an in vivo probe drug in drug-drug interactions studiesseems to be questionable (German et al., 2007).

Of the other potential in vivo probe substrates ofCYP2C8, the two thiazolidinediones pioglitazone androsiglitazone are the best documented. As pointed outin the previous section, CYP2C8 is the main enzymemediating their primary hydroxylation reactions invitro (Baldwin et al., 1999; Jaakkola et al., 2006c).Accordingly, the typical dosing of gemfibrozil 600 mgtwice daily, which has been estimated to cause over 95%inhibition of CYP2C8 (Fig. 9; Honkalammi et al., 2012),increased the AUC of rosiglitazone about 2.3-fold andthat of pioglitazone 3.2-4.3-fold, simultaneously reduc-ing the concentrations of their hydroxyl metabolites(Niemi et al., 2003a; Deng et al., 2005; Jaakkola et al.,2005; Aquilante et al., 2013a). Unlike repaglinide, theyare insensitive to OATP1B1 function (Kalliokoski et al.,2008a). However, they have a long half-life, necessitat-ing an up to 72-hour blood sampling period for a fullpharmacokinetic analysis. On the basis of its betteravailability and sensitivity to CYP2C8 inhibition, pio-glitazone is slightly preferable over rosiglitazone as aCYP2C8 probe.

The leukotriene receptor antagonist montelukast isanother sensitive CYP2C8 substrate that could be usedas a CYP2C8 probe. Gemfibrozil has increased its AUCalmost fivefold and markedly reduced the formation ofits 36-hydroxylated metabolite (Karonen et al., 2010).On the other hand, montelukast is also partiallymetabolized by CYP3A4 in vitro (Filppula et al., 2011;VandenBrink et al., 2011). However, the strongCYP3A4 inhibitor itraconazole has had no effect onmontelukast concentrations (Karonen et al., 2012),indicating that the role of CYP3A4 in montelukastmetabolism is minor. Moreover, montelukast is notknown to be a substrate for OATP1B1.

In addition to the above substrates, there are someother CYP2C8 substrate drugs that could be used as invivo markers on the basis of their sensitivity to interactwith gemfibrozil. Such drugs include, for example,daprodustat and dasabuvir. However, the former isnot yet on the market, and the second one is expensive,and more documentation is needed before they can berecommended as probe substrates.

3. In Vivo Cytochrome P450 2C8 Probe Inhibitors.Probe inhibitors are needed for studying the contri-bution of CYP2C8 in the metabolism of a new drug, aswell as for documenting the risk of drug-drug interac-tions affecting the drug in vivo. Among clinically usedCYP2C8 inhibitors, gemfibrozil is the strongest known.Its CYP2C8 inhibitory effect is also highly selective dueto the specific mechanism that is mediated via specificCYP2C8 inactivation by the glucuronide metabolite ofgemfibrozil (Ogilvie et al., 2006). In vitro, parentgemfibrozil inhibits CYP2C9 activity with a fairly low

226 Backman et al.

Ki (about 6 mM), but its inhibitory effects on the othermain CYP enzymes are much weaker (Backman et al.,2000; Wen et al., 2001; Wang et al., 2002). In clinicalstudies, gemfibrozil at a dose of 600 mg twice daily hasnot increased the concentrations of the CYP2C9 sub-strate warfarin (Lilja et al., 2005) or had any effect thatcould be due to inhibition of CYP3A4 on the concentra-tions of the parent lactone forms of simvastatin andlovastatin (Backman et al., 2000; Kyrklund et al., 2001).On the other hand, gemfibrozil has drastically, up to18.6-fold, increased the AUCs of CYP2C8 substratedrugs (Fig. 7; Table 10), suggesting that with regard toCYP enzymes, the inhibitory effect of gemfibrozil ishighly selective for CYP2C8.The CYP2C8 inhibitory effect of gemfibrozil is strong,

rapid, and long lasting. In studies using repaglinide asthe CYP2C8 probe substrate, subtherapeutic doses ofgemfibrozil have considerably elevated the concentra-tions of repaglinide (Honkalammi et al., 2011a, 2012),and it has been estimated that the clinically usedgemfibrozil dosing (600 mg twice daily) inhibitsCYP2C8 activity by about 99% and that one-tenth ofthis dose would already lead to more than 90% in-hibition of CYP2C8 (Fig. 9). Although CYP2C8 inhi-bition by gemfibrozil is based on time-dependentinactivation of the enzyme by the primary glucuronidemetabolite of gemfibrozil, CYP2C8 inhibition occursrapidly after gemfibrozil dosing. When repaglinidewas given 0, 1, 3, or 6 hours after a single 600 mg doseof gemfibrozil, the AUC of repaglinide was increased5.0-, 6.3-, 6.6-, and 5.4-fold, respectively, indicating thatstrong inhibition of CYP2C8 can be achieved almostimmediately after a single dose of gemfibrozil (Fig. 8,Honkalammi et al., 2011b). It has also been demon-strated that the CYP2C8 inhibitory effect of gemfibrozilpersists virtually unchanged throughout the typical12-hour dosing interval of gemfibrozil (Tornio et al.,2008a). Thus, gemfibrozil can have a strong effect onCYP2C8 substrates, irrespective of their half-life ortime of daily dosing relative to gemfibrozil administra-tion (Fig. 9; Table 10), making it an ideal in vivo probeinhibitor of CYP2C8. The only caveat with gemfibrozil isthat it is also a moderate inhibitor of OATP1B1 andOAT3 and can therefore also increase the concentra-tions of some drugs that are not or only partiallymetabolized by CYP2C8 (Kyrklund et al., 2001, 2003;Backman et al., 2002; Schneck et al., 2004; Neuvonenet al., 2006; Whitfield et al., 2011).Compared with gemfibrozil, all other clinically docu-

mented CYP2C8 inhibitors seem to be suboptimal.Trimethoprim is relatively selective for CYP2C8, butas expected from its in vitro inhibitory effects (Wenet al., 2002), it is only a weak CYP2C8 inhibitor atclinically feasible doses (Niemi et al., 2004a,b; Hruskaet al., 2005; Tornio et al., 2008b), and therefore it canonly be regarded as a confirmatory CYP2C8 inhibitor invivo. Clopidogrel is the second strongest CYP2C8

inhibitor documented so far, increasing the AUC ofrepaglinide about fivefold (Tornio et al., 2014). Clopi-dogrel is obviously also a useful diagnostic CYP2C8inhibitor, but it is not fully selective and has not beenextensively documented so far. In addition to stronglyinhibiting CYP2C8, clopidogrel is also a moderateinhibitor of CYP2B6 (Turpeinen et al., 2005). Further-more, it has been suspected of causing CYP2C19 in-hibition (Nishiya et al., 2009). However, it seems to havepractically no effect on CYP3A4 or OATP1B1 activitiesin vivo (Tornio et al., 2014; Itkonen et al., 2015).

VIII. Conclusions and Future Prospects

CYP2C8 is one of the main oxidative drug metabo-lizing enzymes in the liver. Its expression and functionhave been studied in detail, and for example, it hasbeen estimated that its in vivo turnover half-life isabout 22 hours in humans. The CYP2C8 gene contains9 exons and shares 74% sequence homology withCYP2C9. More than 100 nonsynonymous CYP2C8SNVs are known to date, but only some of them areassociated with functional variability. Interethnicand geographical differences exist in the frequencyof variants. For example, the low-activity variantCYP2C8*2 (c.805A.T) is common in Africans but rarein Caucasians and Asians. CYP2C8*3 (c.416G.A) andCYP2C8*4 (c.792C.G), on the other hand, are com-mon in Caucasians but rare or absent in Africansand Asians (Fig. 6). The interethnic characterizationand functional activity of variants deserve furtherstudies.

Studies on the role of CYP2C8 in drug metabolismhave demonstrated that it is the most importantenzyme for the elimination of several drugs, such ascerivastatin, montelukast, repaglinide, pioglitazone,and rosiglitazone, whose metabolism had been earlierthought to be attributed mainly to other enzymes.CYP2C8 is crucial also for the biotransformation ofdaprodustat (GSK12788693), enzalutamide, dasabuvir,and many other recently developed new drugs, andoverall, it contributes to the elimination of more than100 drugs. CYP2C8 has a large active site cavity, andit can accommodate and also metabolize certain acylglucuronides, such as desloratadine, diclofenac, andsipoglitazar glucuronides.

In vitro, there are several marker reactions for theassessment of CYP2C8 activity, including paclitaxel6-a-hydroxylation, amodiaquine deethylation, montelu-kast 36-hydroxylation, cerivastatin 6-hydroxylation(M-23 formation), rosiglitazone parahydroxylation, andpioglitazone M-IV formation. Each of these reactionshas its strengths and weaknesses. The use of clinicallyrelevant drug concentrations in vitro is a prerequisitefor the estimation of the contribution of differentCYP enzymes in vivo. Gemfibrozil 1-O-b-glucuronideis potent and selective as a diagnostic inhibitor of


CYP2C8-mediated metabolism in vitro. Quercetin andtrimethoprim are relatively weak and unselective asCYP2C8 inhibitors, whereas montelukast is potentand selective, but suffers from nonspecific proteinbinding. Also clopidogrel acyl 1-b-D-glucuronide may bea suitable in vitro inhibitor, but further documentationis needed.Many drugs are CYP2C8 inhibitors or inducers.

Gemfibrozil is in vivo, unlike in vitro, a potent, irre-versible inhibitor of CYP2C8 via formation of gemfi-brozil 1-O-b-glucuronide, and it is widely used as aprobe inhibitor. Also clopidogrel acyl 1-b-D-glucuronidecauses metabolism-dependent inactivation of CYP2C8,indicating that glucuronidesmay contribute as CYP2C8inhibitors to drug-drug interactions. Also efavirenz,trimethoprim, and several protein kinase inhibitorsare inhibitors of CYP2C8.In vivo studies in humans on the role of CYP2C8

are challenged by the lack of suitable selective probesubstrates, inhibitors, and inducers. Although repagli-nide, pioglitazone, rosiglitazone, and montelukast areuseful probe substrates, they all have their pros andcons, as discussed in the text before. With regard toCYP enzymes, gemfibrozil is a selective inhibitor ofCYP2C8 in vivo. Already very small doses of gemfibrozil,i.e., about 10% of its usual therapeutic dose, rapidlycause a strong and long-lasting inactivation of CYP2C8.However, gemfibrozil is also an inhibitor of OATP1B1and OAT3 transporters, which challenges interpreta-tion of the interaction mechanisms if the CYP2C8substrates are also substrates for these transporters.Rifampin is a very unselective albeit strong inducer ofCYP2C8.If a drug is significantly metabolized by CYP2C8 and

CYP3A4, its concomitant administration with inhibi-tors of both of these enzymes, e.g., with gemfibrozil anditraconazole, can cause a much stronger interactionthan is the sum of their separate effects. Thus, the drug-drug interaction studies performed by using inhibitorsof one enzyme only may greatly underestimate thetrue risks as shown by the clinically very importantCYP2C8-mediated interactions affecting repaglinideor cerivastatin. At least theoretically, small doses ofgemfibrozil or other inhibitors of CYPC8 could beused as a booster to optimize the pharmacokineticsof CYP2C8 substrate drugs or to prevent formation ofpotentially toxic metabolites via CYP2C8-mediatedreaction.

Acknowledgments

The authors thank Dr. Tommi Nyrönen for producing the dockingsimulations and three-dimensional artwork in Fig. 2.Backman, Niemi, and Neuvonen have filed a patent application

concerning use of gemfibrozil as a pharmacokinetic enhancer.Some of the information in Tables 1, 3 and 6 is based on the UW

Metabolism and Transport Drug Interaction Database (DIDB),Copyright University of Washington 1999–2015, as specified in thefootnotes to the tables.

Authorship Contributions

Participated in research design: Backman, Filppula, Niemi, andNeuvonen.Wrote or contributed to the writing of the manuscript: Backman,

Filppula, Niemi, and Neuvonen.

References1000 Genomes Project Consortium, Abecasis GR, Auton A, Brooks LD, DePristo MA,Durbin RM, Handsaker RE, Kang HM, Marth GT, and McVean GA; (2012) Anintegrated map of genetic variation from 1,092 human genomes.Nature 491:56–65.

Abass K, Turpeinen M, and Pelkonen O (2009) An evaluation of the cytochrome P450inhibition potential of selected pesticides in human hepatic microsomes. J EnvironSci Health B 44:553–563.

Achour B, Barber J, and Rostami-Hodjegan A (2014) Expression of hepatic drug-metabolizing cytochrome p450 enzymes and their intercorrelations: a meta-anal-ysis. Drug Metab Dispos 42:1349–1356.

Adjei GO, Kristensen K, Goka BQ, Hoegberg LC, Alifrangis M, Rodrigues OP,and Kurtzhals JA (2008) Effect of concomitant artesunate administration and cy-tochrome P4502C8 polymorphisms on the pharmacokinetics of amodiaquine inGhanaian children with uncomplicated malaria. Antimicrob Agents Chemother 52:4400–4406.

Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, KondrashovAS, and Sunyaev SR (2010) A method and server for predicting damaging missensemutations. Nat Methods 7:248–249.

Agúndez JA, García-Martín E, and Martínez C (2009) Genetically based impairment inCYP2C8- and CYP2C9-dependent NSAID metabolism as a risk factor for gastroin-testinal bleeding: is a combination of pharmacogenomics and metabolomics requiredto improve personalized medicine? Expert Opin Drug Metab Toxicol 5:607–620.

Akande AA, Olugbenga SJ, Adebanjoi AJ, Toyin AS, and Ogobna OC (2015) Effects ofco-trimoxazole co-administration on the pharmacokinetics of amodiaquine inhealthy volunteers. Int J Pharm Pharm Sci 7:9; 272–276.

Albassam AA, Mohamed ME, and Frye RF (2015) Inhibitory effect of six herbalextracts on CYP2C8 enzyme activity in human liver microsomes. Xenobiotica 45:406–412.

Albrecht W, Unger A, Nussler AK, and Laufer S (2008) In vitro metabolism of2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl] acetic acid(licofelone, ML3000), an inhibitor of cyclooxygenase-1 and -2 and 5-lipoxygenase.DrugMetab Dispos 36:894–903.

Ando A, Oshida K, Fukuyama S, Watanabe A, Hashimoto H, and Miyamoto Y (2012)Identification of human cytochrome P450 enzymes involved in the metabolism of anovel к-opioid receptor agonist, nalfurafine hydrochloride. Biopharm Drug Dispos33:257–264.

Ando Y, Shimizu T, Nakamura K, Mushiroda T, Nakagawa T, Kodama T,and Kamataki T (1998) Potent and non-specific inhibition of cytochrome P450 byJM216, a new oral platinum agent. Br J Cancer 78:1170–1174.

Aquilante CL, Bushman LR, Knutsen SD, Burt LE, Rome LC, and Kosmiski LA(2008) Influence of SLCO1B1 and CYP2C8 gene polymorphisms on rosiglitazonepharmacokinetics in healthy volunteers. Hum Genomics 3:7–16.

Aquilante CL, Kosmiski LA, Bourne DW, Bushman LR, Daily EB, Hammond KP,Hopley CW, Kadam RS, Kanack AT, and Kompella UB (2013a) Impact of theCYP2C8 *3 polymorphism on the drug-drug interaction between gemfibrozil andpioglitazone. Br J Clin Pharmacol 75:217–226.

Aquilante CL, Niemi M, Gong L, Altman RB, and Klein TE (2013b) PharmGKBsummary: very important pharmacogene information for cytochrome P450, family2, subfamily C, polypeptide 8. Pharmacogenet Genomics 23:721–728.

Aquilante CL, Wempe MF, Spencer SH, Kosmiski LA, Predhomme JA, and SidhomMS (2013c) Influence of CYP2C8*2 on the pharmacokinetics of pioglitazone inhealthy African-American volunteers. Pharmacotherapy 33:1000–1007.

Arbus C, Benyamina A, Llorca PM, Baylé F, Bromet N, Massiere F, Garay RP,and Hameg A (2007) Characterization of human cytochrome P450 enzymes in-volved in the metabolism of cyamemazine. Eur J Pharm Sci 32:357–366.

Arnaldo P, Thompson RE, Lopes MQ, Suffys PN, and Santos AR (2013) Frequenciesof cytochrome P450 2B6 and 2C8 allelic variants in the mozambican population.Malays J Med Sci 20:13–23.

Arun KP, Meda VS, Kucherlapati VSP, Dubala A, Deepalakshmi M, Anand Vijaya-Kumar PR, Elango K, and Suresh B (2012) Pharmacokinetic drug interaction be-tween gemfibrozil and sitagliptin in healthy Indian male volunteers. Eur J ClinPharmacol 68:709–714.

Arun Kumar AS, Kumar SS, Umamaheswaran G, Kesavan R, Balachandar J,and Adithan C (2015) Association of CYP2C8, CYP2C9 and CYP2J2 gene poly-morphisms with myocardial infarction in South Indian population. Pharmacol Rep67:97–101.

Attar M, Dong D, Ling KH, and Tang-Liu DD (2003) Cytochrome P450 2C8 andflavin-containing monooxygenases are involved in the metabolism of tazarotenicacid in humans. Drug Metab Dispos 31:476–481.

Backman JT, Honkalammi J, Neuvonen M, Kurkinen KJ, Tornio A, Niemi M,and Neuvonen PJ (2009) CYP2C8 activity recovers within 96 hours after gemfi-brozil dosing: estimation of CYP2C8 half-life using repaglinide as an in vivo probe.Drug Metab Dispos 37:2359–2366.

Backman JT, Kajosaari LI, Neuvonen M, and Neuvonen PJ (2003) Trimethoprimincreases the plasma concentrations of cerivastatin by inhibiting its CYP2C8-mediated metabolism, Abstract in 8th European ISSX Meeting, Dijon, France(April 27-May 1, 2003).

Backman JT, Kyrklund C, Kivistö KT, Wang JS, and Neuvonen PJ (2000) Plasmaconcentrations of active simvastatin acid are increased by gemfibrozil. ClinPharmacol Ther 68:122–129.

Backman JT, Kyrklund C, Neuvonen M, and Neuvonen PJ (2002) Gemfibrozil greatlyincreases plasma concentrations of cerivastatin. Clin Pharmacol Ther 72:685–691.

228 Backman et al.

Bae SH, Kwon MJ, Park JB, Kim D, Kim DH, Kang JS, Kim CG, Oh E, and Bae SK(2014) Metabolic drug-drug interaction potential of macrolactin A and 7-O-succinylmacrolactin A assessed by evaluating cytochrome P450 inhibition and inductionand UDP-glucuronosyltransferase inhibition in vitro. Antimicrob Agents Chemo-ther 58:5036–5046.

Baer BR, DeLisle RK, and Allen A (2009) Benzylic oxidation of gemfibrozil-1-O-beta-glucuronide by P450 2C8 leads to heme alkylation and irreversible inhibition.Chem Res Toxicol 22:1298–1309.

Bahadur N, Leathart JB, Mutch E, Steimel-Crespi D, Dunn SA, Gilissen R, HoudtJV, Hendrickx J, Mannens G, and Bohets H (2002) CYP2C8 polymorphisms inCaucasians and their relationship with paclitaxel 6alpha-hydroxylase activity inhuman liver microsomes. Biochem Pharmacol 64:1579–1589.

Balla B, Vaszilko M, Kósa JP, Podani J, Takács I, Tóbiás B, Nagy Z, Lazáry A,and Lakatos P (2012) New approach to analyze genetic and clinical data inbisphosphonate-induced osteonecrosis of the jaw. Oral Dis 18:580–585.

Bajpai P, Srinivasan S, Ghosh J, Nagy LD, Wei S, Guengerich FP, and Avadhani NG(2014) Targeting of splice variants of human cytochrome P450 2C8 (CYP2C8) tomitochondria and their role in arachidonic acid metabolism and respiratory dys-function. J Biol Chem 289:29614–29630.

Baldwin SJ, Clarke SE, and Chenery RJ (1999) Characterization of the cytochromeP450 enzymes involved in the in vitro metabolism of rosiglitazone. Br J ClinPharmacol 48:424–432.

Ballard JE, Prueksaritanont T, and Tang C (2007) Hepatic metabolism of MK-0457, apotent aurora kinase inhibitor: interspecies comparison and role of human cyto-chrome P450 and flavin-containing monooxygenase. Drug Metab Dispos 35:1447–1451.

Barbosa-Sicard E, Markovic M, Honeck H, Christ B, Muller DN, and Schunck WH(2005) Eicosapentaenoic acid metabolism by cytochrome P450 enzymes of theCYP2C subfamily. Biochem Biophys Res Commun 329:1275–1281.

Baune B, Flinois JP, Furlan V, Gimenez F, Taburet AM, Becquemont L,and Farinotti R (1999) Halofantrine metabolism in microsomes in man: major roleof CYP 3A4 and CYP 3A5. J Pharm Pharmacol 51:419–426.

Becquemont L, Mouajjah S, Escaffre O, Beaune P, Funck-Brentano C, and Jaillon P(1999) Cytochrome P-450 3A4 and 2C8 are involved in zopiclone metabolism. DrugMetab Dispos 27:1068–1073.

Bergmann TK, Brasch-Andersen C, Gréen H, Mirza M, Pedersen RS, Nielsen F,Skougaard K, Wihl J, Keldsen N, and Damkier P (2011) Impact of CYP2C8*3 onpaclitaxel clearance: a population pharmacokinetic and pharmacogenomic study in93 patients with ovarian cancer. Pharmacogenomics J 11:113–120.

Bergmann TK, Filppula AM, Launiainen T, Nielsen F, Backman JT, and Brosen K(2015) Neurotoxicity and low paclitaxel clearance associated with concomitantclopidogrel therapy in a 60 year old Caucasian woman with ovarian carcinoma.Br J Clin Pharmacol doi: 10.1111/bcp.12795.

Bidstrup TB, Bjørnsdottir I, Sidelmann UG, Thomsen MS, and Hansen KT (2003)CYP2C8 and CYP3A4 are the principal enzymes involved in the human in vitrobiotransformation of the insulin secretagogue repaglinide. Br J Clin Pharmacol 56:305–314.

Bidstrup TB, Damkier P, Olsen AK, Ekblom M, Karlsson A, and Brøsen K (2006) Theimpact of CYP2C8 polymorphism and grapefruit juice on the pharmacokinetics ofrepaglinide. Br J Clin Pharmacol 61:49–57.

Bidstrup TB, Stilling N, Damkier P, Scharling B, Thomsen MS, and Brøsen K (2004)Rifampicin seems to act as both an inducer and an inhibitor of the metabolism ofrepaglinide. Eur J Clin Pharmacol 60:109–114.

Blanco JG, Harrison PL, Evans WE, and Relling MV (2000) Human cytochrome P450maximal activities in pediatric versus adult liver. Drug Metab Dispos 28:379–382.

Boberg M, Angerbauer R, Fey P, Kanhai WK, Karl W, Kern A, Ploschke J,and Radtke M (1997) Metabolism of cerivastatin by human liver microsomes invitro. Characterization of primary metabolic pathways and of cytochrome P450isozymes involved. Drug Metab Dispos 25:321–331.

Bogman K, Silkey M, Chan SP, Tomlinson B, and Weber C (2010) Influence ofCYP2C19 genotype on the pharmacokinetics of R483, a CYP2C19 substrate, inhealthy subjects and type 2 diabetes patients. Eur J Clin Pharmacol 66:1005–1015.

Bonierbale E, Valadon P, Pons C, Desfosses B, Dansette PM, and Mansuy D (1999)Opposite behaviors of reactive metabolites of tienilic acid and its isomer towardliver proteins: use of specific anti-tienilic acid-protein adduct antibodies and thepossible relationship with different hepatotoxic effects of the two compounds. ChemRes Toxicol 12:286–296.

Bort R, Gómez-Lechón MJ, Castell JV, and Jover R (2004) Role of hepatocyte nuclearfactor 3 gamma in the expression of human CYP2C genes. Arch Biochem Biophys426:63–72.

Bu HZ, Zhao P, Kang P, Pool WF, and Wu EY (2006) Identification of enzymesresponsible for primary and sequential oxygenation reactions of capravirine inhuman liver microsomes. Drug Metab Dispos 34:1798–1802.

Bun SS, Ciccolini J, Bun H, Aubert C, and Catalin J (2003) Drug interactions ofpaclitaxel metabolism in human liver microsomes. J Chemother 15:266–274.

Burnett BP, Pillai L, Bitto A, Squadrito F, and Levy RM (2011) Evaluation of CYP450inhibitory effects and steady-state pharmacokinetics of genistein in combinationwith cholecalciferol and citrated zinc bisglycinate in postmenopausal women. Int JWomens Health 3:139–150.

Busse D, Cosme J, Beaune P, Kroemer HK, and EichelbaumM (1995) Cytochromes ofthe P450 2C subfamily are the major enzymes involved in the O-demethylation ofverapamil in humans. Naunyn Schmiedebergs Arch Pharmacol 353:116–121.

Bymaster FP, Chao P, Schulze H, Tran PV, and Marshall RD (2013) Bio-pharmaceutical characterization, metabolism, and brain penetration of the triplereuptake inhibitor amitifadine. Drug Metab Lett 7:23–33.

Cai X, Wang RW, Edom RW, Evans DC, Shou M, Rodrigues AD, Liu W, Dean DC,and Baillie TA (2004) Validation of (-)-N-3-benzyl-phenobarbital as a selective in-hibitor of CYP2C19 in human liver microsomes. Drug Metab Dispos 32:584–586.

Cameron MD, Wright J, Black CB, and Ye N (2007) In vitro prediction and in vivoverification of enantioselective human tofisopam metabolite profiles. Drug MetabDispos 35:1894–1902.

Capozzi ME, McCollum GW, and Penn JS (2014) The role of cytochrome P450epoxygenases in retinal angiogenesis. Invest Ophthalmol Vis Sci 55:4253–4260.

Cardoso JO, Oliveira RV, Lu JB, and Desta Z (2015) In vitro metabolism of mon-telukast by cytochrome P450s (CYPs) and UDP-glucuronosyltransferases(UGTs). Drug Metab Dispos 10.1124/dmd.115.065763.

Cavaco I, Mårtensson A, Fröberg G, Msellem M, Björkman A, and Gil JP (2013)CYP2C8 status of patients with malaria influences selection of Plasmodium fal-ciparum pfmdr1 alleles after amodiaquine-artesunate treatment. J Infect Dis 207:687–688.

Cavaco I, Piedade R, Gil JP, and Ribeiro V (2006) CYP2C8 polymorphism among thePortuguese. Clin Chem Lab Med 44:168–170.

Cavaco I, Strömberg-Nörklit J, Kaneko A, Msellem MI, Dahoma M, Ribeiro VL,Bjorkman A, and Gil JP (2005) CYP2C8 polymorphism frequencies among malariapatients in Zanzibar. Eur J Clin Pharmacol 61:15–18.

Cazali N, Tran A, Treluyer JM, Rey E, d’Athis P, Vincent J, and Pons G (2003)Inhibitory effect of stiripentol on carbamazepine and saquinavir metabolism inhuman. Br J Clin Pharmacol 56:526–536.

Chang JT, Staffa JA, Parks M, and Green L (2004) Rhabdomyolysis with HMG-CoAreductase inhibitors and gemfibrozil combination therapy. PharmacoepidemiolDrug Saf 13:417–426.

Chang SY, Chen C, Yang Z, and Rodrigues AD (2009) Further assessment of 17alpha-ethinyl estradiol as an inhibitor of different human cytochrome P450 forms in vitro.Drug Metab Dispos 37:1667–1675.

Chang SY, Li W, Traeger SC, Wang B, Cui D, Zhang H, Wen B, and Rodrigues AD(2008) Confirmation that cytochrome P450 2C8 (CYP2C8) plays a minor role in (S)-(+)-and (R)-(-)-ibuprofen hydroxylation in vitro. Drug Metab Dispos 36:2513–2522.

Chang TK, Weber GF, Crespi CL, and Waxman DJ (1993) Differential activation ofcyclophosphamide and ifosphamide by cytochromes P-450 2B and 3A in humanliver microsomes. Cancer Res 53:5629–5637.

Chang TK, Yu L, Maurel P, and Waxman DJ (1997) Enhanced cyclophosphamide andifosfamide activation in primary human hepatocyte cultures: response to cyto-chrome P-450 inducers and autoinduction by oxazaphosphorines. Cancer Res 57:1946–1954.

Chang Y, Fang WB, Lin SN, and Moody DE (2011) Stereo-selective metabolism ofmethadone by human liver microsomes and cDNA-expressed cytochrome P450s: areconciliation. Basic Clin Pharmacol Toxicol 108:55–62.

Chang Y, Moody DE, and McCance-Katz EF (2006) Novel metabolites of buprenor-phine detected in human liver microsomes and human urine. Drug Metab Dispos34:440–448.

Chen C and Wang DW (2015) Cytochrome P450-CYP2 family-epoxygenase role ininflammation and cancer. Adv Pharmacol 74:193–221.

Chen X, Kosoglou T, Statkevich P, Kumar B, Li J, Dockendorf MF, Wang G, Lowe RS,Jiang J, and Liu H (2014) Pharmacokinetics of vorapaxar and its metabolite fol-lowing oral administration in healthy Chinese and American subjects. Int J ClinPharmacol Ther 52:889–899.

Chen Y, Coulter S, Jetten AM, and Goldstein JA (2009) Identification of humanCYP2C8 as a retinoid-related orphan nuclear receptor target gene. J PharmacolExp Ther 329:192–201.

Chen Y and Goldstein JA (2009) The transcriptional regulation of the human CYP2Cgenes. Curr Drug Metab 10:567–578.

Cherstniakova SA, Bi D, Fuller DR, Mojsiak JZ, Collins JM, and Cantilena LR(2001) Metabolism of vanoxerine, 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine, by human cytochrome P450 enzymes. Drug Metab Dispos29:1216–1220.

Chiba M, Xu X, Nishime JA, Balani SK, and Lin JH (1997) Hepatic microsomalmetabolism of montelukast, a potent leukotriene D4 receptor antagonist, in hu-mans. Drug Metab Dispos 25:1022–1031.

Choi SY, Koh KH, and Jeong H (2013) Isoform-specific regulation of cytochromesP450 expression by estradiol and progesterone. Drug Metab Dispos 41:263–269.

Churchill FC, Patchen LC, Campbell CC, Schwartz IK, Nguyen-Dinh P,and Dickinson CM (1985) Amodiaquine as a prodrug: importance of metabolite(s)in the antimalarial effect of amodiaquine in humans. Life Sci 36:53–62.

Cizkova K, Konieczna A, Erdosova B, and Ehrmann J (2014) Time-dependent ex-pression of cytochrome p450 epoxygenases during human prenatal development.Organogenesis 10:53–61.

Cresteil T, Monsarrat B, Alvinerie P, Tréluyer JM, Vieira I, and Wright M (1994)Taxol metabolism by human liver microsomes: identification of cytochrome P450isozymes involved in its biotransformation. Cancer Res 54:386–392.

Cresteil T, Monsarrat B, Dubois J, Sonnier M, Alvinerie P, and Gueritte F (2002)Regioselective metabolism of taxoids by human CYP3A4 and 2C8: structure-activity relationship. Drug Metab Dispos 30:438–445.

Dai D, Zeldin DC, Blaisdell JA, Chanas B, Coulter SJ, Ghanayem BI, and GoldsteinJA (2001) Polymorphisms in human CYP2C8 decrease metabolism of the anti-cancer drug paclitaxel and arachidonic acid. Pharmacogenetics 11:597–607.

Daikh BE, Lasker JM, Raucy JL, and Koop DR (1994) Regio- and stereoselectiveepoxidation of arachidonic acid by human cytochromes P450 2C8 and 2C9. JPharmacol Exp Ther 271:1427–1433.

Daily EB and Aquilante CL (2009) Cytochrome P450 2C8 pharmacogenetics: a reviewof clinical studies. Pharmacogenomics 10:1489–1510.

Damle BD, Dowell JA, Walsky RL, Weber GL, Stogniew M, and Inskeep PB (2009) Invitro and in vivo studies to characterize the clearance mechanism and potentialcytochrome P450 interactions of anidulafungin. Antimicrob Agents Chemother 53:1149–1156.

Davis JA, Rock DA, Wienkers LC, and Pearson JT (2012) In vitro characterization ofthe drug-drug interaction potential of catabolites of antibody-maytansinoid con-jugates. Drug Metab Dispos 40:1927–1934.


Dekhuijzen PN and Koopmans PP (2002) Pharmaokinetic profile of zafirlukast. ClinPharmacokinet 41:105–114.

Delaforge M, Pruvost A, Perrin L, and André F (2005) Cytochrome P450-mediatedoxidation of glucuronide derivatives: example of estradiol-17beta-glucuronide oxi-dation to 2-hydroxy-estradiol-17beta-glucuronide by CYP 2C8. Drug Metab Dispos33:466–473.

Delozier TC, Kissling GE, Coulter SJ, Dai D, Foley JF, Bradbury JA, Murphy E,Steenbergen C, Zeldin DC, and Goldstein JA (2007) Detection of human CYP2C8,CYP2C9, and CYP2J2 in cardiovascular tissues. Drug Metab Dispos 35:682–688.

Deng LJ, Wang F, and Li HD (2005) Effect of gemfibrozil on the pharmacokinetics ofpioglitazone. Eur J Clin Pharmacol 61:831–836.

Derks M, Fowler S, and Kuhlmann O (2009) In vitro and in vivo assessment of theeffect of dalcetrapib on a panel of CYP substrates. Curr Med Res Opin 25:891–902.

Desai PB, Duan JZ, Zhu YW, and Kouzi S (1998) Human liver microsomal metabolismof paclitaxel and drug interactions. Eur J Drug Metab Pharmacokinet 23:417–424.

Desta Z, Soukhova N, Mahal SK, and Flockhart DA (2000) Interaction of cisapridewith the human cytochrome P450 system: metabolism and inhibition studies. DrugMetab Dispos 28:789–800.

Desta Z, Soukhova N, Morocho AM, and Flockhart DA (2001) Stereoselective me-tabolism of cisapride and enantiomer-enantiomer interaction in human cytochromeP450 enzymes: major role of CYP3A. J Pharmacol Exp Ther 298:508–520.

Desta Z, Ward BA, Soukhova NV, and Flockhart DA (2004) Comprehensive evalua-tion of tamoxifen sequential biotransformation by the human cytochrome P450system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther310:1062–1075.

Dierks EA, Stams KR, Lim HK, Cornelius G, Zhang H, and Ball SE (2001) A methodfor the simultaneous evaluation of the activities of seven major human drug-metabolizing cytochrome P450s using an in vitro cocktail of probe substrates andfast gradient liquid chromatography tandem mass spectrometry. Drug MetabDispos 29:23–29.

Dinger J, Meyer MR, and Maurer HH (2014) Development of an in vitro cytochromeP450 cocktail inhibition assay for assessing the inhibition risk of drugs of abuse.Toxicol Lett 230:28–35.

Dixit V, Hariparsad N, Li F, Desai P, Thummel KE, and Unadkat JD (2007) Cyto-chrome P450 enzymes and transporters induced by anti-human immunodeficiencyvirus protease inhibitors in human hepatocytes: implications for predicting clinicaldrug interactions. Drug Metab Dispos 35:1853–1859.

Doecke CJ, Sansom LN, and McManus ME (1990) Phenytoin 4-hydroxylation byrabbit liver P450IIC3 and identification of orthologs in human liver microsomes.Biochem Biophys Res Commun 166:860–866.

Doehmer J, Weiss G, McGregor GP, and Appel K (2011) Assessment of a dry extractfrom milk thistle (Silybum marianum) for interference with human livercytochrome-P450 activities. Toxicol In Vitro 25:21–27.

Donato MT, Jiménez N, Castell JV, and Gómez-Lechón MJ (2004) Fluorescence-based assays for screening nine cytochrome P450 (P450) activities in intact cellsexpressing individual human P450 enzymes. Drug Metab Dispos 32:699–706.

Dong PP, Fang ZZ, Zhang YY, Ge GB, Mao YX, Zhu LL, Qu YQ, Li W, Wang LM,and Liu CX (2011) Substrate-dependent modulation of the catalytic activity ofCYP3A by erlotinib. Acta Pharmacol Sin 32:399–407.

Duester G (2008) Retinoic acid synthesis and signaling during early organogenesis.Cell 134:921–931.

Dussault I, Lin M, Hollister K, Wang EH, Synold TW, and Forman BM (2001)Peptide mimetic HIV protease inhibitors are ligands for the orphan receptor SXR.J Biol Chem 276:33309–33312.

Dutheil F, Dauchy S, Diry M, Sazdovitch V, Cloarec O, Mellottée L, Bièche I,Ingelman-Sundberg M, Flinois JP, de Waziers I, Beaune P, Declèves X, DuyckaertsC, and Loriot MA (2009) Xenobiotic-metabolizing enzymes and transporters in thenormal human brain: regional and cellular mapping as a basis for putative roles incerebral function. Drug Metab Dispos 37:1528–1538.

Eagling VA, Howe JL, Barry MJ, and Back DJ (1994) The metabolism of zidovudineby human liver microsomes in vitro: formation of 39-amino-39-deoxythymidine.Biochem Pharmacol 48:267–276.

Eckland DA and Danhof M (2000) Clinical pharmacokinetics of pioglitazone. Exp ClinEndocrinol Diabetes 108 (Suppl 2):S234–S242.

Elliot DJ, Suharjono, Lewis BC, Gillam EM, Birkett DJ, Gross AS, and Miners JO(2007) Identification of the human cytochromes P450 catalysing the rate-limitingpathways of gliclazide elimination. Br J Clin Pharmacol 64:450–457.

Enayetallah AE, French RA, Thibodeau MS, and Grant DF (2004) Distribution ofsoluble epoxide hydrolase and of cytochrome P450 2C8, 2C9, and 2J2 in humantissues. J Histochem Cytochem 52:447–454.

EMA (2012a) Assessment report: Zytiga. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/002321/WC500137814.pdf (Accessed September 15, 2015).

EMA (2012b) Guideline on the investigation of drug interactions. Available from:http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/07/WC500129606.pdf (Accessed September 15, 2015).

EMA (2012c) Summary of product characteristics: Xalkori. Available from: http://ec.europa.eu/health/documents/community-register/2012/20121023124213/anx_124213_en.pdf(Accessed September 15, 2015).

EMA (2012d) Zelboraf, Procedural steps taken and scientific information after theauthorisation. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Procedural_steps_taken_and_scientific_information_after_authorisation/human/002409/WC500137805.pdf (Accessed September 15, 2015).

EMA (2014) Summary of product characteristics: Simbrinza. Available from: http://ec.europa.eu/health/documents/community-register/2014/20140718129060/anx_129060_en.pdf(Accessed September 15, 2015).

Engel G, Hofmann U, Heidemann H, Cosme J, and Eichelbaum M (1996) Antipyrineas a probe for human oxidative drug metabolism: identification of the cytochromeP450 enzymes catalyzing 4-hydroxyantipyrine, 3-hydroxymethylantipyrine, andnorantipyrine formation. Clin Pharmacol Ther 59:613–623.

English BC, Baum CE, Adelberg DE, Sissung TM, Kluetz PG, Dahut WL, Price DK,and Figg WD (2010) A SNP in CYP2C8 is not associated with the development ofbisphosphonate-related osteonecrosis of the jaw in men with castrate-resistantprostate cancer. Ther Clin Risk Manag 6:579–583.

Erve JC, Gauby S, Maynard JW Jr, Svensson MA, Tonn G, and Quinn KP (2013)Bioactivation of sitaxentan in liver microsomes, hepatocytes, and expressed humanP450s with characterization of the glutathione conjugate by liquid chromatographytandem mass spectrometry. Chem Res Toxicol 26:926–936.

Fan G, Cao Y, and Yang J (2015) In vitro inhibition and induction of human cyto-chrome P450 enzymes by SIPI5357, a potential antidepressant. Biopharm DrugDispos 10.1002/bdd.1947.

Fan L, Zhou G, Guo D, Liu YL, Chen WQ, Liu ZQ, Tan ZR, Sheng D, Zhou HH,and Zhang W (2011) The pregnane X receptor agonist St John’s Wort has no effectson the pharmacokinetics and pharmacodynamics of repaglinide. Clin Pharmaco-kinet 50:605–611.

Fasinu PS, Gutmann H, Schiller H, Bouic PJ, and Rosenkranz B (2013a) The po-tential of Hypoxis hemerocallidea for herb-drug interaction. Pharm Biol 51:1499–1507.

Fasinu PS, Gutmann H, Schiller H, James AD, Bouic PJ, and Rosenkranz B (2013b)The potential of Sutherlandia frutescens for herb-drug interaction. Drug MetabDispos 41:488–497.

FDA (1998) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Singulair. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/98/020829s000_Singular_Clin_Pharm_Biopharm.pdf(Accessed September 15, 2015).

FDA (1999) Actos prescribing information. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/1999/21073lbl.pdf (Accessed September 15, 2015).

FDA (2001) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Gleevec. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/21-335_Gleevec_biopharmr_P1.pdf (Accessed Sep-tember 15, 2015).

FDA (2004) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Tarceva. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_biopharmr.pdf (Accessed Septem-ber 15, 2015).

FDA (2005a) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Exjade. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021882_s000_Exjade_BioPharmr.pdf (Accessed Sep-tember 15, 2015).

FDA (2005b) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review: Nevaxar. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_BioPharmR.pdf (Accessed Sep-tember 15, 2015).

FDA (2006a) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Sprycel. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021986s000_Sprycel__ClinPharmR.pdf (Accessed Sep-tember 15, 2015).

FDA (2006b) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review: Sutent. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021938_S000_Sutent_BioPharmR.pdf (Accessed Sep-tember 15, 2015).

FDA (2007a) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Bystolic. Available from: www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021742s000_ClinPharmR_P1.pdf (Accessed September15, 2015).

FDA (2007b) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Neupro. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021829s000_ClinPharmR_P2.pdf (Accessed Sep-tember 15, 2015).

FDA (2007c) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Tasigna. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf (Accessed September15, 2015).

FDA (2007d) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Torisel. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022088s000_ClinPharmR.pdf (Accessed September15, 2015).

FDA (2007e) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Tykerb. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022059s000_ClinPharmR.pdf (Accessed September15, 2015).

FDA (2008a) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Intelence. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/022187s000_ClinPharmR_P5.pdf (Accessed Sep-tember 15, 2015).

FDA (2008b) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Pristiq. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/021992s000_ClinPharmR_P2.pdf (Accessed Sep-tember 15, 2015).

FDA (2008c) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Promacta. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/022291s000_ClinPharmR_P1.pdf (Accessed Sep-tember 15, 2015).

FDA (2009a) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Multaq. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022425s000_ClinPharm_P1.pdf (Accessed Septem-ber 15, 2015).

FDA (2009b) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Tyvaso. Available from: http://www.accessdata.fda.

230 Backman et al.

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/002321/WC500137814.pdf



http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/07/WC500129606.pdf

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/07/WC500129606.pdf

http://ec.europa.eu/health/documents/community-register/2012/20121023124213/anx_124213_en.pdf


http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Procedural_steps_taken_and_scientific_information_after_authorisation/human/002409/WC500137805.pdf





http://www.accessdata.fda.gov/drugsatfda_docs/nda/98/020829s000_Singular_Clin_Pharm_Biopharm.pdf

http://www.accessdata.fda.gov/drugsatfda_docs/nda/98/020829s000_Singular_Clin_Pharm_Biopharm.pdf

http://www.accessdata.fda.gov/drugsatfda_docs/label/1999/21073lbl.pdf

http://www.accessdata.fda.gov/drugsatfda_docs/label/1999/21073lbl.pdf

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/21-335_Gleevec_biopharmr_P1.pdf

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/21-335_Gleevec_biopharmr_P1.pdf

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_biopharmr.pdf

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_biopharmr.pdf

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021882_s000_Exjade_BioPharmr.pdf

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021882_s000_Exjade_BioPharmr.pdf

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_BioPharmR.pdf

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_s000_Nexavar_BioPharmR.pdf

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021986s000_Sprycel__ClinPharmR.pdf

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021986s000_Sprycel__ClinPharmR.pdf

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021938_S000_Sutent_BioPharmR.pdf

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021938_S000_Sutent_BioPharmR.pdf

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021742s000_ClinPharmR_P1.pdf




http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf












http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022425s000_ClinPharm_P1.pdf

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022425s000_ClinPharm_P1.pdf

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022387s000ClinPharmR.pdf

gov/drugsatfda_docs/nda/2009/022387s000ClinPharmR.pdf (Accessed September15, 2015).

FDA (2009c) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Uloric. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/021856s000_ClinPharmR_P1.pdf (Accessed September15, 2015).

FDA (2009d) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Votrient. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022465s000_ClinPharmR.pdf (Accessed September15, 2015).

FDA (2010a) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Jevtana. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/201023s000ClinPharmR.pdf (Accessed September15, 2015).

FDA (2010b) Centre for drug evaluation and research: Pharmacology review(s):Ella. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022474s000PharmR.pdf (Accessed September 15, 2015).

FDA (2011a) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Arcapta Neohaler. Available from: www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022383Orig1s000ClinPharmR.pdf (Accessed Sep-tember 15, 2015).

FDA (2011b) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Brilinta. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022433Orig1s000ClinPharmR.pdf (Accessed Sep-tember 15, 2015).

FDA (2011c) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Edarbi. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/200796Orig1s000ClinPharmR.pdf (Accessed Sep-tember 15, 2015).

FDA (2011d) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Edurant. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202022Orig1s000ClinPharmR.pdf (Accessed Sep-tember 15, 2015).

FDA (2011e) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Xalkori. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202570Orig1s000ClinPharmR.pdf (Accessed Sep-tember 15, 2015).

FDA (2011f) Centre for drug evaluation and research: Pharmacology review(s):Edarbi. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/200796Orig1s000PharmR.pdf (Accessed September 15, 2015).

FDA (2011g) Centre for drug evaluation and research: Pharmacology review(s):Viibryd. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022567Orig1s000ClinPharmR.pdf (Accessed September 15, 2015).

FDA (2012a) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Aubagio. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202992Orig1s000ClinpharmR.pdf (Accessed Sep-tember 15, 2015).

FDA (2012b) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Belviq. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/022529Orig1s000ClinPharmR.pdf (Accessed September15, 2015).

FDA (2012c) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Cometriq. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203756Orig1s000ClinPharmR.pdf (Accessed Sep-tember 15, 2015).

FDA (2012d) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Eliquis. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202155Orig1s000ClinPharmR.pdf (Accessed Sep-tember 15, 2015).

FDA (2012e) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Iclusig. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000ClinPharmR.pdf (Accessed Sep-tember 15, 2015).

FDA (2012f) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Inlyta. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202324Orig1s000ClinPharmR.pdf (Accessed September15, 2015).

FDA (2012g) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Kalydeco. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203188Orig1s000ClinPharmR.pdf (Accessed Sep-tember 15, 2015).

FDA (2012h) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Signifor. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/200677Orig1s000ClinPharmR.pdf (Accessed Sep-tember 15, 2015).

FDA (2012i) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Stivarga. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203085Orig1s000ClinPharmR.pdf (Accessed Sep-tember 15, 2015).

FDA (2012j) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Stribild. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203100Orig1s000ClinPharmR.pdf (Accessed Sep-tember 15, 2015).

FDA (2012k) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Xtandi. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203415Orig1s000ClinPharmR.pdf (Accessed Sep-tember 15, 2015).

FDA (2012l) Centre for drug evaluation and research: Pharmacology review(s):Aubagio. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202992Orig1s000PharmR.pdf (Accessed September 15, 2015).

FDA (2013a) Actos prescribing information. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021073s046lbl.pdf (Accessed September 15, 2015).

FDA (2013b) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Adempas. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204819Orig1s000ClinPharmR.pdf (Accessed Sep-tember 15, 2015).

FDA (2013c) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Breo Ellipta. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204275Orig1s000ClinPharmR.pdf (Accessed Sep-tember 15, 2015).

FDA (2013d) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Imbruvica. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205552Orig1s000ClinPharmR.pdf (Accessed Sep-tember 15, 2015).

FDA (2013e) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Invokana. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf (Accessed Sep-tember 15, 2015).

FDA (2013f) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Mekinist. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204114Orig1s000ClinPharmR.pdf (Accessed Sep-tember 15, 2015).

FDA (2013g) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Nesina. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/022271Orig1s000ClinPharmR.pdf (Accessed Sep-tember 15, 2015).

FDA (2013h) Centre for drug evaluation and research: Clinical pharmacology and bio-pharmaceutics review(s): Olysio. Available from: http://www.accessdata.fda.gov/drug-satfda_docs/nda/2013/205123Orig1s000ClinPharmR.pdf (Accessed September 15, 2015).

FDA (2013i) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Osphena. Available from: www.accessdata.fda.gov/drugsatfda_docs/nda/2013/203505Orig1s000ClinPharmR.pdf (Accessed September15, 2015).

FDA (2013j) Centre for drug evaluation and research: Pharmacology review(s):Brintellix. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204447Orig1s000ClinPharmR.pdf (Accessed September 15, 2015).

FDA (2013k) Centre for drug evaluation and research: Pharmacology review(s):Opsumit. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000PharmR.pdf (Accessed September 15, 2015).

FDA (2014a) Avandia, prescribing information. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021071s047s048s049lbl.pdf (Accessed September15, 2015).

FDA (2014b) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Akynzeo. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205718Orig1s000ClinPharmR.pdf (Accessed Sep-tember 15, 2015).

FDA (2014c) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Beleodaq. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206256Orig1s000ClinPharmR.pdf (Accessed Sep-tember 15, 2015).

FDA (2014d) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Ofev. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205832Orig1s000ClinPharmR.pdf (Accessed September15, 2015).

FDA (2014e) Centre for drug evaluation and research: Clinical pharmacology and bio-pharmaceutics review(s): Otezla. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205437Orig1s000ClinPharmR.pdf (Accessed September15, 2015).

FDA (2014f) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Respimat. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/203108Orig1s000ClinPharmR.pdf (Accessed Sep-tember 15, 2015).

FDA (2014g) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Viekira Pak. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206619Orig1s000ClinPharmR.pdf (AccessedSeptember 15, 2015).

FDA (2014h) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Zydelig. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206545Orig1s000ClinPharmR.pdf (Accessed Sep-tember 15, 2015).

FDA (2014i) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Zykadia. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205755Orig1s000ClinPharmR.pdf (Accessed Sep-tember 15, 2015).

FDA (2014j) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review: Belsomra. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204569Orig1s000ClinPharmR.pdf (Accessed Sep-tember 15, 2015).

FDA (2014k) Centre for drug evaluation and research: Pharmacology review(s):Viekira Pak. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206619Orig1s000PharmR.pdf (Accessed September 15, 2015).

FDA (2014l) Centre for drug evaluation and research: Pharmacology review(s):Zontivity. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204886Orig1s000PharmR.pdf (Accessed September 15, 2015).

FDA (2014m) Hetlioz, prescribing information. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205677Orig1s000ClinPharmR.pdf (Accessed Sep-tember 15, 2015).

FDA (2015a) Centre for drug evaluation and research: Clinical pharmacology andbiopharmaceutics review(s): Lenvima. Available from: http://www.accessdata.fda.









http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022474s000PharmR.pdf

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022474s000PharmR.pdf

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022383Orig1s000ClinPharmR.pdf










http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/200796Orig1s000PharmR.pdf




http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202992Orig1s000ClinpharmR.pdf

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202992Orig1s000ClinpharmR.pdf























http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021073s046lbl.pdf

http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021073s046lbl.pdf





















http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021071s047s048s049lbl.pdf

http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021071s047s048s049lbl.pdf


























gov/drugsatfda_docs/nda/2015/206947Orig1s000ClinPharmR.pdf (Accessed Sep-tember 15, 2015).

FDA (2015b) Reyataz prescribing information. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021567s037,206352s002lbl.pdf (Accessed Sep-tember 15, 2015).

Feidt DM, Klein K, Hofmann U, Riedmaier S, Knobeloch D, Thasler WE, Weiss TS,Schwab M, and Zanger UM (2010) Profiling induction of cytochrome p450 enzymeactivity by statins using a new liquid chromatography-tandem mass spectrometrycocktail assay in human hepatocytes. Drug Metab Dispos 38:1589–1597.

Feng R, Zhou X, Tan XS, Or PM, Hu T, Fu J, Ma JY, Huang M, He CY, and Shi JG(2014) In vitro identification of cytochrome P450 isoforms responsible for the me-tabolism of 1-hydroxyl-2,3,5-trimethoxy-xanthone purified from Halenia ellipticaD. Don. Chem Biol Interact 210:12–19.

Ferguson SS, Chen Y, LeCluyse EL, Negishi M, and Goldstein JA (2005) HumanCYP2C8 is transcriptionally regulated by the nuclear receptors constitutiveandrostane receptor, pregnane X receptor, glucocorticoid receptor, and hepaticnuclear factor 4alpha. Mol Pharmacol 68:747–757.

Filppula AM, Laitila J, Neuvonen PJ, and Backman JT (2011) Reevaluation of themicrosomal metabolism of montelukast: major contribution by CYP2C8 at clini-cally relevant concentrations. Drug Metab Dispos 39:904–911.

Filppula AM, Laitila J, Neuvonen PJ, and Backman JT (2012) Potent mechanism-based inhibition of CYP3A4 by imatinib explains its liability to interact withCYP3A4 substrates. Br J Pharmacol 165:2787–2798.

Filppula AM, Neuvonen M, Laitila J, Neuvonen PJ, and Backman JT (2013a)Autoinhibition of CYP3A4 leads to important role of CYP2C8 in imatinib metab-olism: variability in CYP2C8 activity may alter plasma concentrations and re-sponse. Drug Metab Dispos 41:50–59.

Filppula AM, Neuvonen PJ, and Backman JT (2014) In vitro assessment of time-dependent inhibitory effects on CYP2C8 and CYP3A activity by fourteen proteinkinase inhibitors. Drug Metab Dispos 42:1202–1209.

Filppula AM, Tornio A, Niemi M, Neuvonen PJ, and Backman JT (2013b) Gemfi-brozil impairs imatinib absorption and inhibits the CYP2C8-mediated formation ofits main metabolite. Clin Pharmacol Ther 94:383–393.

Fischer V, Johanson L, Heitz F, Tullman R, Graham E, Baldeck JP, and RobinsonWT (1999) The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor flu-vastatin: effect on human cytochrome P-450 and implications for metabolic druginteractions. Drug Metab Dispos 27:410–416.

Fischer V, Rodríguez-Gascón A, Heitz F, Tynes R, Hauck C, Cohen D, and Vickers AE(1998) The multidrug resistance modulator valspodar (PSC 833) is metabolized byhuman cytochrome P450 3A. Implications for drug-drug interactions and phar-macological activity of the main metabolite. Drug Metab Dispos 26:802–811.

Flaherty KT, Lathia C, Frye RF, Schuchter L, Redlinger M, Rosen M, and O’DwyerPJ (2011) Interaction of sorafenib and cytochrome P450 isoenzymes in patientswith advanced melanoma: a phase I/II pharmacokinetic interaction study. CancerChemother Pharmacol 68:1111–1118.

Fleming I (2014) The pharmacology of the cytochrome P450 epoxygenase/solubleepoxide hydrolase axis in the vasculature and cardiovascular disease. PharmacolRev 66:1106–1140.

Floyd JS, Kaspera R, Marciante KD, Weiss NS, Heckbert SR, Lumley T, Wiggins KL,Tamraz B, Kwok PY, and Totah RA (2012) A screening study of drug-drug inter-actions in cerivastatin users: an adverse effect of clopidogrel. Clin Pharmacol Ther91:896–904.

Foti RS, Pearson JT, Rock DA, Wahlstrom JL, and Wienkers LC (2009) In vitroinhibition of multiple cytochrome P450 isoforms by xanthone derivatives frommangosteen extract. Drug Metab Dispos 37:1848–1855.

Foti RS, Pearson JT, Wong SL, Zalikowski JA, Boudreaux MD, Prokop SP, Davis JA,Banfield C, Emery MG, and Rock DA (2012) Predicting the drug interaction po-tential of AMG 853, a dual antagonist of the D-prostanoid and chemoattractantreceptor-homologous molecule expressed on T helper 2 cells receptors. Drug MetabDispos 40:2239–2249.

Frank A and Unger M (2006) Analysis of frankincense from various Boswellia specieswith inhibitory activity on human drug metabolising cytochrome P450 enzymesusing liquid chromatography mass spectrometry after automated on-line extrac-tion. J Chromatogr A 1112:255–262.

Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, Huttunen JK,Kaitaniemi P, Koskinen P, and Manninen V (1987) Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety oftreatment, changes in risk factors, and incidence of coronary heart disease. N EnglJ Med 317:1237–1245.

Fujino H, Saito T, Tsunenari Y, Kojima J, and Sakaeda T (2004) Metabolic propertiesof the acid and lactone forms of HMG-CoA reductase inhibitors. Xenobiotica 34:961–971.

Fujino H, Shimada S, Yamada I, Hirano M, Tsunenari Y, and Kojima J (2003a)Studies on the interaction between fibrates and statins using human hepatic mi-crosomes. Arzneimittelforschung 53:701–707.

Fujino H, Yamada I, Shimada S, and Yoneda M (2001) Simultaneous determinationof taxol and its metabolites in microsomal samples by a simple thin-layer chro-matography radioactivity assay–inhibitory effect of NK-104, a new inhibitor ofHMG-CoA reductase. J Chromatogr B Biomed Sci Appl 757:143–150.

Fujino H, Yamada I, Shimada S, Hirano M, Tsunenari Y, and Kojima J (2003b)Interaction between fibrates and statins–metabolic interactions with gemfibrozil.Drug Metabol Drug Interact 19:161–176.

Furuta S, Kamada E, Sugimoto T, Kawabata Y, Wu XC, Skibbe J, Usuki E, ParkinsonA, and Kurimoto T (2004) Involvement of CYP2C8 and UGT1A9 in the metabolism ofa novel gastroprokinetic agent, Z-338, in 2nd Pharmaceutical Sciences World Con-gress, Kyoto, Japan (May 31-June 5, 2004). Available from: http://www.cerep.fr/cerep/Users/pages/News/Publications/92.pdf (Accessed June 18, 2015).

Gallemann D, Wimmer E, Höfer CC, Freisleben A, Fluck M, Ladstetter B, and DolgosH (2010) In vitro characterization of sarizotan metabolism: hepatic clearance,identification and characterization of metabolites, drug-metabolizing enzyme

identification, and evaluation of cytochrome p450 inhibition. Drug Metab Dispos38:905–916.

Gan J, Chen W, Shen H, Gao L, Hong Y, Tian Y, Li W, Zhang Y, Tang Y, and Zhang H(2010) Repaglinide-gemfibrozil drug interaction: inhibition of repaglinide glucur-onidation as a potential additional contributing mechanism. Br J Clin Pharmacol70:870–880.

Gan J, Liu-Kreyche P, and Humphreys WG (2012) In vitro assessment of cytochromeP450 inhibition and induction potential of tanespimycin and its major metabolite,17-amino-17-demethoxygeldanamycin. Cancer Chemother Pharmacol 69:51–56.

Gao Y, Liu D, Wang H, Zhu J, and Chen C (2010) Functional characterization of fiveCYP2C8 variants and prediction of CYP2C8 genotype-dependent effects on in vitroand in vivo drug-drug interactions. Xenobiotica 40:467–475.

García-Martín E, Martínez C, Ladero JM, and Agúndez JA (2006) Interethnic andintraethnic variability of CYP2C8 and CYP2C9 polymorphisms in healthy indi-viduals. Mol Diagn Ther 10:29–40.

García-Martín E, Martínez C, Tabarés B, Frías J, and Agúndez JA (2004) In-terindividual variability in ibuprofen pharmacokinetics is related to interaction ofcytochrome P450 2C8 and 2C9 amino acid polymorphisms. Clin Pharmacol Ther76:119–127.

Gerbal-Chaloin S, Daujat M, Pascussi JM, Pichard-Garcia L, Vilarem MJ,and Maurel P (2002) Transcriptional regulation of CYP2C9 gene. Role of gluco-corticoid receptor and constitutive androstane receptor. J Biol Chem 277:209–217.

Gerbal-Chaloin S, Pascussi JM, Pichard-Garcia L, Daujat M, Waechter F, Fabre JM,Carrère N, and Maurel P (2001) Induction of CYP2C genes in human hepatocytesin primary culture. Drug Metab Dispos 29:242–251.

German P, Greenhouse B, Coates C, Dorsey G, Rosenthal PJ, Charlebois E, LindegardhN, Havlir D, and Aweeka FT (2007) Hepatotoxicity due to a drug interaction betweenamodiaquine plus artesunate and efavirenz. Clin Infect Dis 44:889–891.

Ghosal A, Chowdhury SK, Tong W, Hapangama N, Yuan Y, Su AD, and Zbaida S(2006) Identification of human liver cytochrome P450 enzymes responsible for themetabolism of lonafarnib (Sarasar). Drug Metab Dispos 34:628–635.

Ghosal A, Hapangama N, Yuan Y, Lu X, Horne D, Patrick JE, and Zbaida S (2003)Rapid determination of enzyme activities of recombinant human cytochromes P450,human liver microsomes and hepatocytes. Biopharm Drug Dispos 24:375–384.

Gibbons JA, de Vries M, Krauwinkel W, Ohtsu Y, Noukens J, van der Walt JS, Mol R,Mordenti J, and Ouatas T (2015) Pharmacokinetic drug interaction studies withEnzalutamide. Clin Pharmacokinet 54:1057–1069.

Gil JP and Gil Berglund E (2007) CYP2C8 and antimalaria drug efficacy. Pharma-cogenomics 8:187–198.

Gorman GS, Coward L, Kerstner-Wood C, Cork L, Kapetanovic IM, Brouillette WJ,and Muccio DD (2007) In vitro metabolic characterization, phenotyping, and ki-netic studies of 9cUAB30, a retinoid X receptor-specific retinoid. Drug MetabDispos 35:1157–1164.

Grace JM, Skanchy DJ, and Aguilar AJ (1999) Metabolism of artelinic acid to dihy-droqinqhaosu by human liver cytochrome P4503A. Xenobiotica 29:703–717.

Gray IC, Nobile C, Muresu R, Ford S, and Spurr NK (1995) A 2.4-megabase physicalmap spanning the CYP2C gene cluster on chromosome 10q24. Genomics 28:328–332.

Gréen H, Khan MS, Jakobsen-Falk I, Åvall-Lundqvist E, and Peterson C (2011)Impact of CYP3A5*3 and CYP2C8-HapC on paclitaxel/carboplatin-induced mye-losuppression in patients with ovarian cancer. J Pharm Sci 100:4205–4209.

Grimm SW and Dyroff MC (1997) Inhibition of human drug metabolizing cyto-chromes P450 by anastrozole, a potent and selective inhibitor of aromatase. DrugMetab Dispos 25:598–602.

Grimm SW, Einolf HJ, Hall SD, He K, Lim HK, Ling KH, Lu C, Nomeir AA, SeibertE, and Skordos KW (2009) The conduct of in vitro studies to address time-dependent inhibition of drug-metabolizing enzymes: a perspective of the pharma-ceutical research and manufacturers of America. Drug Metab Dispos 37:1355–1370.

Guitton J, Buronfosse T, Desage M, Flinois JP, Perdrix JP, Brazier JL, and Beaune P(1998) Possible involvement of multiple human cytochrome P450 isoforms in theliver metabolism of propofol. Br J Anaesth 80:788–795.

Guo J, Nikolic D, Chadwick LR, Pauli GF, and van Breemen RB (2006) Identificationof human hepatic cytochrome P450 enzymes involved in the metabolism of 8-pre-nylnaringenin and isoxanthohumol from hops (Humulus lupulus L.). Drug MetabDispos 34:1152–1159.

Ha-Duong NT, Dijols S, Macherey AC, Goldstein JA, Dansette PM, and Mansuy D(2001) Ticlopidine as a selective mechanism-based inhibitor of human cytochromeP450 2C19. Biochemistry 40:12112–12122.

Hagihara K, Nishiya Y, Kurihara A, Kazui M, Farid NA, and Ikeda T (2008) Com-parison of human cytochrome P450 inhibition by the thienopyridines prasugrel,clopidogrel, and ticlopidine. Drug Metab Pharmacokinet 23:412–420.

Hakkola J, Pasanen M, Purkunen R, Saarikoski S, Pelkonen O, Mäenpää J, Rane A,and Raunio H (1994) Expression of xenobiotic-metabolizing cytochrome P450 formsin human adult and fetal liver. Biochem Pharmacol 48:59–64.

Hall M, Matthews A, Paul DS, Foster JR, Holding JD, Islam K, and Brandt RD(2007)Interactions of Iclaprim with Human Cytochrome P450 Enzymes, in 8th In-ternational ISSX Meeting, Sendai, Japan; (October 9–12). Available from: http://issx.confex.com/issx/intl8/webprogram/Paper6798.html (Accessed August 26, 2015).

Halling J, Petersen MS, Damkier P, Nielsen F, Grandjean P, Weihe P, Lundgren S,Lundblad MS, and Brøsen K (2005) Polymorphism of CYP2D6, CYP2C19, CYP2C9and CYP2C8 in the Faroese population. Eur J Clin Pharmacol 61:491–497.

Hamitouche S, Poupon J, Dreano Y, Amet Y, and Lucas D (2006) Ethanol oxidationinto acetaldehyde by 16 recombinant human cytochrome P450 isoforms: role ofCYP2C isoforms in human liver microsomes. Toxicol Lett 167:221–230.

Hamman MA, Thompson GA, and Hall SD (1997) Regioselective and stereoselectivemetabolism of ibuprofen by human cytochrome P450 2C. Biochem Pharmacol 54:33–41.

Handschin C and Meyer UA (2003) Induction of drug metabolism: the role of nuclearreceptors. Pharmacol Rev 55:649–673.

232 Backman et al.


http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021567s037,206352s002lbl.pdf

http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021567s037,206352s002lbl.pdf

http://www.cerep.fr/cerep/Users/pages/News/Publications/92.pdf

http://www.cerep.fr/cerep/Users/pages/News/Publications/92.pdf

http://issx.confex.com/issx/intl8/webprogram/Paper6798.html


Hanioka N, Matsumoto K, Saito Y, and Narimatsu S (2010) Functional character-ization of CYP2C8.13 and CYP2C8.14: catalytic activities toward paclitaxel. BasicClin Pharmacol Toxicol 107:565–569.

Hanioka N, Matsumoto K, Saito Y, and Narimatsu S (2011) Influence of CYP2C8*13and CYP2C8*14 alleles on amiodarone N-deethylation. Basic Clin PharmacolToxicol 108:359–362.

Harris JW, Rahman A, Kim BR, Guengerich FP, and Collins JM (1994) Metabolismof taxol by human hepatic microsomes and liver slices: participation of cytochromeP450 3A4 and an unknown P450 enzyme. Cancer Res 54:4026–4035.

Hatorp V, Hansen KT, and Thomsen MS (2003) Influence of drugs interacting withCYP3A4 on the pharmacokinetics, pharmacodynamics, and safety of the prandialglucose regulator repaglinide. J Clin Pharmacol 43:649–660.

He M, Jiang J, Qiu F, Liu S, Peng P, Gao C, and Miao P (2013) Inhibitory effects ofgypenosides on seven human cytochrome P450 enzymes in vitro. Food ChemToxicol 57:262–265.

Henningsson A, Marsh S, Loos WJ, Karlsson MO, Garsa A, Mross K, Mielke S,Viganò L, Locatelli A, and Verweij J (2005) Association of CYP2C8, CYP3A4,CYP3A5, and ABCB1 polymorphisms with the pharmacokinetics of paclitaxel. ClinCancer Res 11:8097–8104.

Hertz DL, Motsinger-Reif AA, Drobish A, Winham SJ, McLeod HL, Carey LA,and Dees EC (2012) CYP2C8*3 predicts benefit/risk profile in breast cancer pa-tients receiving neoadjuvant paclitaxel. Breast Cancer Res Treat 134:401–410.

Hertz DL, Roy S, Jack J, Motsinger-Reif AA, Drobish A, Clark LS, Carey LA, DeesEC, and McLeod HL (2014) Genetic heterogeneity beyond CYP2C8*3 does notexplain differential sensitivity to paclitaxel-induced neuropathy. Breast Cancer ResTreat 145:245–254.

Hichiya H, Tanaka-Kagawa T, Soyama A, Jinno H, Koyano S, Katori N, MatsushimaE, Uchiyama S, Tokunaga H, and Kimura H (2005) Functional characterization offive novel CYP2C8 variants, G171S, R186X, R186G, K247R, and K383N, found in aJapanese population. Drug Metab Dispos 33:630–636.

Hidestrand M, Oscarson M, Salonen JS, Nyman L, Pelkonen O, Turpeinen M,and Ingelman-Sundberg M (2001) CYP2B6 and CYP2C19 as the major enzymesresponsible for the metabolism of selegiline, a drug used in the treatment of Par-kinson’s disease, as revealed from experiments with recombinant enzymes. DrugMetab Dispos 29:1480–1484.

Hirano M, Maeda K, Shitara Y, and Sugiyama Y (2006) Drug-drug interaction be-tween pitavastatin and various drugs via OATP1B1. Drug Metab Dispos 34:1229–1236.

Hiratsuka M, Hinai Y, Sasaki T, Konno Y, Imagawa K, Ishikawa M, and Mizugaki M(2007) Characterization of human cytochrome p450 enzymes involved in the me-tabolism of cilostazol. Drug Metab Dispos 35:1730–1732.

Hokkanen J, Tolonen A, Mattila S, and Turpeinen M (2011) Metabolism of hyper-forin, the active constituent of St. John’s wort, in human liver microsomes. Eur JPharm Sci 42:273–284.

Holmberg MT, Tornio A, Neuvonen M, Neuvonen PJ, Backman JT, and Niemi M(2014) Grapefruit juice inhibits the metabolic activation of clopidogrel. ClinPharmacol Ther 95:307–313.

Hong SP, Lusiak BD, Burback BL, and Johnson JD (2013) Evaluations of in vitrometabolism, drug-drug interactions mediated by reversible and time-dependentinhibition of CYPs, and plasma protein binding of MMB4 DMS. Int J Toxicol32(4, Suppl):75S–87S.

Honkalammi J, Niemi M, Neuvonen PJ, and Backman JT (2011a) Dose-dependentinteraction between gemfibrozil and repaglinide in humans: strong inhibition ofCYP2C8 with subtherapeutic gemfibrozil doses. Drug Metab Dispos 39:1977–1986.

Honkalammi J, Niemi M, Neuvonen PJ, and Backman JT (2011b) Mechanism-basedinactivation of CYP2C8 by gemfibrozil occurs rapidly in humans. Clin PharmacolTher 89:579–586.

Honkalammi J, Niemi M, Neuvonen PJ, and Backman JT (2012) Gemfibrozil is astrong inactivator of CYP2C8 in very small multiple doses. Clin Pharmacol Ther91:846–855.

Houston JB and Galetin A (2008) Methods for predicting in vivo pharmacokineticsusing data from in vitro assays. Curr Drug Metab 9:940–951.

Hruska MW, Amico JA, Langaee TY, Ferrell RE, Fitzgerald SM, and Frye RF (2005)The effect of trimethoprim on CYP2C8 mediated rosiglitazone metabolism in hu-man liver microsomes and healthy subjects. Br J Clin Pharmacol 59:70–79.

Hu G, Johnson EF, and Kemper B (2010) CYP2C8 exists as a dimer in naturalmembranes. Drug Metab Dispos 38:1976–1983.

Hu M, Krausz K, Chen J, Ge X, Li J, Gelboin HL, and Gonzalez FJ (2003) Identifi-cation of CYP1A2 as the main isoform for the phase I hydroxylated metabolism ofgenistein and a prodrug converting enzyme of methylated isoflavones. Drug MetabDispos 31:924–931.

Huang SM, Strong JM, Zhang L, Reynolds KS, Nallani S, Temple R, Abraham S,Habet SA, Baweja RK, and Burckart GJ (2008) New era in drug interactionevaluation: US Food and Drug Administration update on CYP enzymes, trans-porters, and the guidance process. J Clin Pharmacol 48:662–670.

Huang Z, Roy P, and Waxman DJ (2000) Role of human liver microsomal CYP3A4and CYP2B6 in catalyzing N-dechloroethylation of cyclophosphamide and ifosfa-mide. Biochem Pharmacol 59:961–972.

Ibarra-Barrueta O, Palacios-Zabalza I, Mora-Atorrasagasti O, and Mayo-Suarez J(2014) Effect of concomitant use of montelukast and efavirenz on neuropsychiatricadverse events. Ann Pharmacother 48:145–148.

Illingworth NA, Boddy AV, Daly AK, and Veal GJ (2011) Characterization of themetabolism of fenretinide by human liver microsomes, cytochrome P450 enzymesand UDP-glucuronosyltransferases. Br J Pharmacol 162:989–999.

Im Y, Kim YW, Song IS, Joo J, Shin JH, Wu Z, Lee HS, Park KH, and Liu KH (2012)Effect of TSHAC on human cytochrome P450 activity, and transport mediated byP-glycoprotein. J Microbiol Biotechnol 22:1659–1664.

Inoue S, Howgate EM, Rowland-Yeo K, Shimada T, Yamazaki H, Tucker GT,and Rostami-Hodjegan A (2006) Prediction of in vivo drug clearance from in vitrodata. II: potential inter-ethnic differences. Xenobiotica 36:499–513.

Iribarne C, Berthou F, Baird S, Dréano Y, Picart D, Bail JP, Beaune P, and Ménez JF(1996) Involvement of cytochrome P450 3A4 enzyme in the N-demethylation ofmethadone in human liver microsomes. Chem Res Toxicol 9:365–373.

Itkonen MK, Tornio A, Neuvonen M, Neuvonen PJ, Niemi M, and Backman JT(2015) Clopidogrel has no clinically meaningful effect on the pharmacokinetics ofthe OATP1B1 and CYP3A4 substrate simvastatin. Drug Metab Dispos 43:1655–1660.

Jaakkola T, Backman JT, Neuvonen M, Laitila J, and Neuvonen PJ (2006a) Effect ofrifampicin on the pharmacokinetics of pioglitazone. Br J Clin Pharmacol 61:70–78.

Jaakkola T, Backman JT, Neuvonen M, and Neuvonen PJ (2005) Effects of gemfi-brozil, itraconazole, and their combination on the pharmacokinetics of pioglitazone.Clin Pharmacol Ther 77:404–414.

Jaakkola T, Backman JT, Neuvonen M, Niemi M, and Neuvonen PJ (2006b) Mon-telukast and zafirlukast do not affect the pharmacokinetics of the CYP2C8 sub-strate pioglitazone. Eur J Clin Pharmacol 62:503–509.

Jaakkola T, Laitila J, Neuvonen PJ, and Backman JT (2006c) Pioglitazone ismetabolised by CYP2C8 and CYP3A4 in vitro: potential for interactions withCYP2C8 inhibitors. Basic Clin Pharmacol Toxicol 99:44–51.

Jacobsen W, Christians U, and Benet LZ (2000a) In vitro evaluation of the dispositionof A novel cysteine protease inhibitor. Drug Metab Dispos 28:1343–1351.

Jacobsen W, Kuhn B, Soldner A, Kirchner G, Sewing KF, Kollman PA, Benet LZ,and Christians U (2000b) Lactonization is the critical first step in the disposition ofthe 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor atorvastatin. Drug MetabDispos 28:1369–1378.

Jacobsen W, Serkova N, Hausen B, Morris RE, Benet LZ, and Christians U (2001)Comparison of the in vitro metabolism of the macrolide immunosuppressantssirolimus and RAD. Transplant Proc 33:514–515.

Jancová P, Anzenbacherová E, Papousková B, Lemr K, Luzná P, Veinlichová A,Anzenbacher P, and Simánek V (2007) Silybin is metabolized by cytochrome P4502C8 in vitro. Drug Metab Dispos 35:2035–2039.

Jenkins SM, Zvyaga T, Johnson SR, Hurley J, Wagner A, Burrell R, Turley W, LeetJE, Philip T, and Rodrigues AD (2011) Studies to further investigate the inhibitionof human liver microsomal CYP2C8 by the acyl-b-glucuronide of gemfibrozil. DrugMetab Dispos 39:2421–2430.

Jeong HU, Kong TY, Kwon SS, Hong SW, Yeon SH, Choi JH, Lee JY, Cho YY,and Lee HS (2013) Effect of honokiol on cytochrome P450 and UDP-glucuronosyltransferase enzyme activities in human liver microsomes. Molecules18:10681–10693.

Jeong HU, Kwon SS, Kong TY, Kim JH, and Lee HS (2014) Inhibitory effects ofcedrol, b-cedrene, and thujopsene on cytochrome P450 enzyme activities in humanliver microsomes. J Toxicol Environ Health A 77:1522–1532.

Ji HY, Kim SY, Kim DK, Jeong JH, and Lee HS (2010) Effects of eupatilin andjaceosidin on cytochrome p450 enzyme activities in human liver microsomes.Molecules 15:6466–6475.

Ji HY, Lee HW, Kim HH, Choi JK, and Lee HS (2005) Characterization of humanliver cytochrome P450 enzymes involved in the metabolism of a new H+/K+-ATPase inhibitor KR-60436. Toxicol Lett 155:103–114.

Ji HY, Liu KH, Kong TY, Jeong HU, Choi SZ, Son M, Cho YY, and Lee HS (2013)Evaluation of DA-9801, a new herbal drug for diabetic neuropathy, on metabolism-mediated interaction. Arch Pharm Res 36:1–5.

Johansson M, Strahm E, Rane A, and Ekström L (2014) CYP2C8 and CYP2C9 mRNAexpression profile in the human fetus. Front Genet 5:58.

Johnson BM, Stier BA, and Caltabiano S (2014) Effect of food and gemfibrozil on thepharmacokinetics of the novel prolyl hydroxylase inhibitor GSK1278863. ClinPharmacol Drug Develop 3:109–117.

Johnson EF and Stout CD (2005) Structural diversity of human xenobiotic-metabolizing cytochrome P450 monooxygenases. Biochem Biophys Res Commun338:331–336.

Johnson SS, Oyelola FT, Ari T, and Juho H (2013) In vitro inhibitory activities of theextract of Hibiscus sabdariffa L. (family Malvaceae) on selected cytochrome P450isoforms. Afr J Tradit Complement Altern Medicines 10:533–540.

Joo J, Lee D, Wu Z, Shin JH, Lee HS, Kwon BM, Huh TL, Kim YW, Lee SJ, and KimTW (2013) In vitro metabolism of obovatol and its effect on cytochrome P450 en-zyme activities in human liver microsomes. Biopharm Drug Dispos 34:195–202.

Kajosaari LI, Jaakkola T, Neuvonen PJ, and Backman JT (2006a) Pioglitazone, an invitro inhibitor of CYP2C8 and CYP3A4, does not increase the plasma concentra-tions of the CYP2C8 and CYP3A4 substrate repaglinide. Eur J Clin Pharmacol 62:217–223.

Kajosaari LI, Laitila J, Neuvonen PJ, and Backman JT (2005a) Metabolism ofrepaglinide by CYP2C8 and CYP3A4 in vitro: effect of fibrates and rifampicin.Basic Clin Pharmacol Toxicol 97:249–256.

Kajosaari LI, Niemi M, Backman JT, and Neuvonen PJ (2006b) Telithromycin, butnot montelukast, increases the plasma concentrations and effects of the cyto-chrome P450 3A4 and 2C8 substrate repaglinide. Clin Pharmacol Ther 79:231–242.

Kajosaari LI, Niemi M, Neuvonen M, Laitila J, Neuvonen PJ, and Backman JT(2005b) Cyclosporine markedly raises the plasma concentrations of repaglinide.Clin Pharmacol Ther 78:388–399.

Kalgutkar AS, Chen D, Varma MV, Feng B, Terra SG, Scialis RJ, Rotter CJ, Fred-erick KS, West MA, and Goosen TC (2013) Elucidation of the biochemical basis fora clinical drug-drug interaction between atorvastatin and 5-(N-(4-((4-ethylbenzyl)thio)phenyl)sulfamoyl)-2-methyl benzoic acid (CP-778875), a subtype selective ag-onist of the peroxisome proliferator-activated receptor alpha. Xenobiotica 43:963–972.

Kalliokoski A, Backman JT, Kurkinen KJ, Neuvonen PJ, and Niemi M (2008b) Ef-fects of gemfibrozil and atorvastatin on the pharmacokinetics of repaglinide inrelation to SLCO1B1 polymorphism. Clin Pharmacol Ther 84:488–496.

Kalliokoski A, Neuvonen M, Neuvonen PJ, and Niemi M (2008a) No significant effectof SLCO1B1 polymorphism on the pharmacokinetics of rosiglitazone and piogli-tazone. Br J Clin Pharmacol 65:78–86.


Kamali F and Huang ML (1996) Increased systemic availability of loperamide afteroral administration of loperamide and loperamide oxide with cotrimoxazole. Br JClin Pharmacol 41:125–128.

Kamel A, Colizza K, and Obach RS (2013) In vitro metabolism of the 5-hydroxy-tryptamine1B receptor antagonist elzasonan. Xenobiotica 43:368–378.

Kamdem LK, Liu Y, Stearns V, Kadlubar SA, Ramirez J, Jeter S, Shahverdi K, WardBA, Ogburn E, and Ratain MJ (2010) In vitro and in vivo oxidative metabolism andglucuronidation of anastrozole. Br J Clin Pharmacol 70:854–869.

Kaneko K, Suzuki K, Iwadate-Iwata E, Kato I, Uchida K, and Onoue M (2013)Evaluation of food-drug interaction of guava leaf tea. Phytother Res 27:299–305.

Kang P, Dalvie D, Smith E, Zhou S, Deese A, and Nieman JA (2008) Bioactivation offlutamide metabolites by human liver microsomes. Drug Metab Dispos 36:1425–1437.

Kantola T, Kivistö KT, and Neuvonen PJ (1999) Effect of itraconazole on cerivastatinpharmacokinetics. Eur J Clin Pharmacol 54:851–855.

Karam WG, Goldstein JA, Lasker JM, and Ghanayem BI (1996) Human CYP2C19 isa major omeprazole 5-hydroxylase, as demonstrated with recombinant cytochromeP450 enzymes. Drug Metab Dispos 24:1081–1087.

Kara�zniewicz-Łada M, Luczak M, and Główka F (2009) Pharmacokinetic studies ofenantiomers of ibuprofen and its chiral metabolites in humans with different variantsof genes coding CYP2C8 and CYP2C9 isoenzymes. Xenobiotica 39:476–485.

Karlsson FH, Bouchene S, Hilgendorf C, Dolgos H, and Peters SA (2013) Utility of invitro systems and preclinical data for the prediction of human intestinal first-passmetabolism during drug discovery and preclinical development.Drug Metab Dispos41:2033–2046.

Karonen T, Filppula A, Laitila J, Niemi M, Neuvonen PJ, and Backman JT (2010)Gemfibrozil markedly increases the plasma concentrations of montelukast: a pre-viously unrecognized role for CYP2C8 in the metabolism of montelukast. ClinPharmacol Ther 88:223–230.

Karonen T, Neuvonen PJ, and Backman JT (2011) The CYP2C8 inhibitor gemfibrozildoes not affect the pharmacokinetics of zafirlukast. Eur J Clin Pharmacol 67:151–155.

Karonen T, Neuvonen PJ, and Backman JT (2012) CYP2C8 but not CYP3A4 is im-portant in the pharmacokinetics of montelukast. Br J Clin Pharmacol 73:257–267.

Kaspera R, Naraharisetti SB, Evangelista EA, Marciante KD, Psaty BM, and TotahRA (2011) Drug metabolism by CYP2C8.3 is determined by substrate dependentinteractions with cytochrome P450 reductase and cytochrome b5. Biochem Phar-macol 82:681–691.

Kaspera R, Naraharisetti SB, Tamraz B, Sahele T, Cheesman MJ, Kwok PY, MarcianteK, Heckbert SR, Psaty BM, and Totah RA (2010) Cerivastatin in vitro metabolism byCYP2C8 variants found in patients experiencing rhabdomyolysis. PharmacogenetGenomics 20:619–629.

Kassahun K, McIntosh I, Koeplinger K, Sun L, Talaty JE, Miller DL, Dixon R, ZajicS, and Stoch SA (2014) Disposition and metabolism of the cathepsin K inhibitorodanacatib in humans. Drug Metab Dispos 42:818–827.

Kazmi F, Barbara JE, Yerino P, and Parkinson A (2015) A long-standing mysterysolved: the formation of 3-hydroxydesloratadine is catalyzed by CYP2C8 but priorglucuronidation of desloratadine by UDP-glucuronosyltransferase 2B10 is anobligatory requirement. Drug Metab Dispos 43:523–533.

Kazmi F, Haupt LJ, Horkman JR, Smith BD, Buckley DB, Wachter EA, and SingerJM (2014) In vitro inhibition of human liver cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes by rose bengal: system-dependent effectson inhibitory potential. Xenobiotica 44:606–614.

Kazmi F, Smith B, Hvenegaard MG, Bendahl L, Gipson A, Buckley D, Ogilvie B,and Parkinson A (2010) Identification of a novel carbamoyl glucuronide as ametabolism-dependent inhibitor of CYP2C8, in 9th International ISSX Meeting,Istanbul, Turkey (September 4-8, 2010). Available from: https://issx.confex.com/issx/intl9/webprogram/Paper21723.html (Accessed June 6, 2015).

Kerr BM, Thummel KE, Wurden CJ, Klein SM, Kroetz DL, Gonzalez FJ, and LevyRH (1994) Human liver carbamazepine metabolism. Role of CYP3A4 and CYP2C8in 10,11-epoxide formation. Biochem Pharmacol 47:1969–1979.

Khan MS, Barratt DT, and Somogyi AA (2015) Impact of CYP2C8*3 polymorphismon in vitro metabolism of imatinib to N-desmethyl imatinib. Xenobiotica 10:1–10.

Kim DK, Liu KH, Jeong JH, Ji HY, Oh SR, Lee HK, and Lee HS (2011a) In vitrometabolism of magnolin and characterization of cytochrome P450 enzymes re-sponsible for its metabolism in human liver microsomes. Xenobiotica 41:358–371.

Kim H, Kang S, Kim H, Yoon YJ, Cha EY, Lee HS, Kim JH, Yea SS, Lee SS, and ShinJG (2006) In vitro metabolism of a new cardioprotective agent, KR-32570, in hu-man liver microsomes. Rapid Commun Mass Spectrom 20:837–843.

Kim IS, Kim Y, Kwak TH, and Yoo HH (2013a) Effects of b-lapachone, a new anti-cancer candidate, on cytochrome P450-mediated drug metabolism. Cancer Che-mother Pharmacol 72:699–702.

Kim J, Peraire C, Solà J, Johanning KM, Dalton JT, and Veverka KA (2011b) Druginteraction potential of toremifene and N-desmethyltoremifene with multiple cy-tochrome P450 isoforms. Xenobiotica 41:851–862.

Kim KA, Chung J, Jung DH, and Park JY (2004) Identification of cytochrome P450isoforms involved in the metabolism of loperamide in human liver microsomes. EurJ Clin Pharmacol 60:575–581.

Kim KA, Park JY, Lee JS, and Lim S (2003) Cytochrome P450 2C8 and CYP3A4/5 areinvolved in chloroquine metabolism in human liver microsomes. Arch Pharm Res26:631–637.

Kim KA, Park PW, Kim HK, Ha JM, and Park JY (2005a) Effect of quercetin on thepharmacokinetics of rosiglitazone, a CYP2C8 substrate, in healthy subjects. J ClinPharmacol 45:941–946.

Kim KA, Park PW, Kim KR, and Park JY (2007) Effect of multiple doses of mon-telukast on the pharmacokinetics of rosiglitazone, a CYP2C8 substrate, in humans.Br J Clin Pharmacol 63:339–345.

Kim KB, Chesney J, Robinson D, Gardner H, Shi MM, and Kirkwood JM (2011c)Phase I/II and pharmacodynamic study of dovitinib (TKI258), an inhibitor of

fibroblast growth factor receptors and VEGF receptors, in patients with advancedmelanoma. Clin Cancer Res 17:7451–7461.

Kim MJ, Kim H, Cha IJ, Park JS, Shon JH, Liu KH, and Shin JG (2005b) High-throughput screening of inhibitory potential of nine cytochrome P450 enzymes invitro using liquid chromatography/tandem mass spectrometry. Rapid CommunMass Spectrom 19:2651–2658.

Kim MJ, Lee JW, Oh KS, Choi CS, Kim KH, Han WS, Yoon CN, Chung ES, KimDH, and Shin JG (2013b) The tyrosine kinase inhibitor nilotinib selectivelyinhibits CYP2C8 activities in human liver microsomes. Drug Metab Phar-macokinet 28:462–467.

Kim SY, Kang JY, Hartman JH, Park SH, Jones DR, Yun CH, Boysen G, and MillerGP (2012) Metabolism of R- and S-warfarin by CYP2C19 into four hydrox-ywarfarins. Drug Metab Lett 6:157–164.

Kim YW, Kim YK, Kim DK, and Sheen YY (2008) Identification of human cytochromeP450 enzymes involved in the metabolism of IN-1130, a novel activin receptor-likekinase-5 (ALK5) inhibitor. Xenobiotica 38:451–464.

Kirchheiner J, Roots I, Goldammer M, Rosenkranz B, and Brockmöller J (2005)Effect of genetic polymorphisms in cytochrome p450 (CYP) 2C9 and CYP2C8 on thepharmacokinetics of oral antidiabetic drugs: clinical relevance. Clin Pharmacokinet44:1209–1225.

Kirchheiner J, Thomas S, Bauer S, Tomalik-Scharte D, Hering U, Doroshyenko O,Jetter A, Stehle S, Tsahuridu M, and Meineke I (2006) Pharmacokinetics andpharmacodynamics of rosiglitazone in relation to CYP2C8 genotype. Clin Phar-macol Ther 80:657–667.

Kitamura A, Mizuno Y, Natsui K, Yabuki M, Komuro S, and Kanamaru H (2005)Characterization of human cytochrome P450 enzymes involved in the in vitrometabolism of perospirone. Biopharm Drug Dispos 26:59–65.

Klieber S, Arabeyre-Fabre C, Moliner P, Marti E, Mandray M, Ngo R, Ollier C, BrunP, and Fabre G (2014) Identification of metabolic pathways and enzyme systemsinvolved in the in vitro human hepatic metabolism of dronedarone, a potent neworal antiarrhythmic drug. Pharmacol Res Perspect 2:e00044.

Klose TS, Blaisdell JA, and Goldstein JA (1999) Gene structure of CYP2C8 andextrahepatic distribution of the human CYP2Cs. J Biochem Mol Toxicol 13:289–295.

Kochansky CJ, Xia YQ, Wang S, Cato B, Creighton M, Vincent SH, Franklin RB,and Reed JR (2005) Species differences in the elimination of a peroxisomeproliferator-activated receptor agonist highlighted by oxidative metabolism of itsacyl glucuronide. Drug Metab Dispos 33:1894–1904.

Kojima K, Nagata K, Matsubara T, and Yamazoe Y (2007) Broad but distinct role ofpregnane x receptor on the expression of individual cytochrome p450s in humanhepatocytes. Drug Metab Pharmacokinet 22:276–286.

Komatsu K, Ito K, Nakajima Y, Kanamitsu Si, Imaoka S, Funae Y, Green CE, TysonCA, Shimada N, and Sugiyama Y (2000a) Prediction of in vivo drug-drug interac-tions between tolbutamide and various sulfonamides in humans based on in vitroexperiments. Drug Metab Dispos 28:475–481.

Komatsu T, Yamazaki H, Shimada N, Nagayama S, Kawaguchi Y, Nakajima M,and Yokoi T (2001) Involvement of microsomal cytochrome P450 and cytosolicthymidine phosphorylase in 5-fluorouracil formation from tegafur in human liver.Clin Cancer Res 7:675–681.

Komatsu T, Yamazaki H, Shimada N, Nakajima M, and Yokoi T (2000b) Roles ofcytochromes P450 1A2, 2A6, and 2C8 in 5-fluorouracil formation from tegafur, ananticancer prodrug, in human liver microsomes. Drug Metab Dispos 28:1457–1463.

Komoroski BJ, Parise RA, Egorin MJ, Strom SC, and Venkataramanan R (2005)Effect of the St. John’s wort constituent hyperforin on docetaxel metabolism byhuman hepatocyte cultures. Clin Cancer Res 11:6972–6979.

Korprasertthaworn P, Polasek TM, Sorich MJ, McLachlan AJ, Miners JO, TuckerGT, and Rowland A (2015) In vitro characterization of the human liver microsomalkinetics and reaction phenotyping of olanzapine metabolism. Drug Metab Dispos43:1806–1814.

Korzekwa K (2014) Case study 4. Predicting the drug interaction potential for in-hibition of CYP2C8 by montelukast. Methods Mol Biol 1113:461–469.

Korzekwa K, Tweedie D, Argikar UA, Whitcher-Johnstone A, Bell L, Bickford S,and Nagar S (2014) A numerical method for analysis of in vitro time-dependentinhibition data. Part 2. Application to experimental data. Drug Metab Dispos 42:1587–1595.

Kosugi Y, Hirabayashi H, Igari T, Fujioka Y, Okuda T, and Moriwaki T (2014) Riskassessment of drug-drug interactions using hepatocytes suspended in serum dur-ing the drug discovery process. Xenobiotica 44:336–344.

Kot M and Daniel WA (2008) The relative contribution of human cytochrome P450isoforms to the four caffeine oxidation pathways: an in vitro comparative studywith cDNA-expressed P450s including CYP2C isoforms. Biochem Pharmacol 76:543–551.

Kozakai K, Yamada Y, Oshikata M, Kawase T, Suzuki E, Haramaki Y, and TaniguchiH (2012) Reliable high-throughput method for inhibition assay of 8 cytochromeP450 isoforms using cocktail of probe substrates and stable isotope-labeled internalstandards. Drug Metab Pharmacokinet 27:520–529.

Kudo T, Ozaki Y, Kusano T, Hotta E, Oya Y, Komatsu S, Goda H, and Ito K (2015)Effect of buffer conditions on CYP2C8-mediated paclitaxel 6a-hydroxylation andCYP3A4-mediated triazolam a- and 4-hydroxylation by human liver microsomes.Xenobiotica 10.3109/00498254.2015.1071502.

Kudzi W, Dodoo AN, and Mills JJ (2009) Characterisation of CYP2C8, CYP2C9 andCYP2C19 polymorphisms in a Ghanaian population. BMC Med Genet 10:124.

Kumar GN, Dubberke E, Rodrigues AD, Roberts E, and Dennisen JF (1997) Identifica-tion of cytochromes P450 involved in the human liver microsomal metabolism of thethromboxane A2 inhibitor seratrodast (ABT-001). Drug Metab Dispos 25:110–115.

Kumar GN, Walle UK, and Walle T (1994) Cytochrome P450 3A-mediated human livermicrosomal taxol 6 alpha-hydroxylation. J Pharmacol Exp Ther 268:1160–1165.

Kumar P, Henikoff S, and Ng PC (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4:1073–1081.

234 Backman et al.

https://issx.confex.com/issx/intl9/webprogram/Paper21723.html

https://issx.confex.com/issx/intl9/webprogram/Paper21723.html

Kumar S, Samuel K, Subramanian R, Braun MP, Stearns RA, Chiu SH, Evans DC,and Baillie TA (2002) Extrapolation of diclofenac clearance from in vitro micro-somal metabolism data: role of acyl glucuronidation and sequential oxidative me-tabolism of the acyl glucuronide. J Pharmacol Exp Ther 303:969–978.

Kurata N, Nishimura Y, Iwase M, Fischer NE, Tang BK, Inaba T, and Yasuhara H(1998) Trimethadione metabolism by human liver cytochrome P450: evidence forthe involvement of CYP2E1. Xenobiotica 28:1041–1047.

Kyrklund C, Backman JT, Kivistö KT, Neuvonen M, Laitila J, and Neuvonen PJ(2001) Plasma concentrations of active lovastatin acid are markedly increased bygemfibrozil but not by bezafibrate. Clin Pharmacol Ther 69:340–345.

Kyrklund C, Backman JT, Neuvonen M, and Neuvonen PJ (2003) Gemfibrozil in-creases plasma pravastatin concentrations and reduces pravastatin renal clear-ance. Clin Pharmacol Ther 73:538–544.

Lacy S, Hsu B, Miles D, Aftab D, Wang R, and Nguyen L (2015) Metabolism andDisposition of Cabozantinib in Healthy Male Volunteers and PharmacologicCharacterization of Its Major Metabolites. Drug Metab Dispos 43:1190–1207.

Lai XS, Yang LP, Li XT, Liu JP, Zhou ZW, and Zhou SF (2009) Human CYP2C8:structure, substrate specificity, inhibitor selectivity, inducers and polymorphisms.Curr Drug Metab 10:1009–1047.

Läpple F, von Richter O, Fromm MF, Richter T, Thon KP, Wisser H, Griese EU,Eichelbaum M, and Kivistö KT (2003) Differential expression and function ofCYP2C isoforms in human intestine and liver. Pharmacogenetics 13:565–575.

Lawrence SK, Nguyen D, Bowen C, Richards-Peterson L, and Skordos KW (2014) Themetabolic drug-drug interaction profile of Dabrafenib: in vitro investigations and quan-titative extrapolation of the P450-mediated DDI risk. Drug Metab Dispos 42:1180–1190.

Lee CA, Jones JP 3rd, Katayama J, Kaspera R, Jiang Y, Freiwald S, Smith E, WalkerGS, and Totah RA (2012a) Identifying a selective substrate and inhibitor pair forthe evaluation of CYP2J2 activity. Drug Metab Dispos 40:943–951.

Lee HS, Ji HY, Park EJ, and Kim SY (2007) In vitro metabolism of eupatilin bymultiple cytochrome P450 and UDP-glucuronosyltransferase enzymes. Xenobiotica37:803–817.

Lee HS, Park EJ, Ji HY, Kim SY, Im GJ, Lee SM, and Jang IJ (2008) Identification ofcytochrome P450 enzymes responsible for N -dealkylation of a new oral erecto-genic, mirodenafil. Xenobiotica 38:21–33.

Lee KC, Shorr R, Rodriguez R, Maturo C, Boteju LW, and Sheldon A (2011) For-mation and anti-tumor activity of uncommon in vitro and in vivo metabolites ofCPI-613, a novel anti-tumor compound that selectively alters tumor energy me-tabolism. Drug Metab Lett 5:163–182.

Lee M, Park J, Lim MS, Seong SJ, Lee J, Seo JJ, Park YK, Lee HW, and Yoon YR(2012b) High-throughput screening of inhibitory effects of Bo-yang-hwan-o-tang onhuman cytochrome P450 isoforms in vitro using UPLC/MS/MS. Anal Sci 28:1197–1201.

Lee MY, Apellániz-Ruiz M, Johansson I, Vikingsson S, Bergmann TK, Brøsen K,Green H, Rodríguez-Antona C, and Ingelman-Sundberg M (2015) Role of cyto-chrome P450 2C8*3 (CYP2C8*3) in paclitaxel metabolism and paclitaxel-inducedneurotoxicity. Pharmacogenomics doi:10.2217/pgs.15.46.

Lee TM, Huang L, Johnson MK, Lizak P, Kroetz D, Aweeka F, and Parikh S (2012c)In vitro metabolism of piperaquine is primarily mediated by CYP3A4. Xenobiotica42:1088–1095.

Leo MA, Lasker JM, Raucy JL, Kim CI, Black M, and Lieber CS (1989) Metabolism ofretinol and retinoic acid by human liver cytochrome P450IIC8. Arch BiochemBiophys 269:305–312.

Leskelä S, Jara C, Leandro-García LJ, Martínez A, García-Donas J, Hernando S,Hurtado A, Vicario JC, Montero-Conde C, and Landa I (2011) Polymorphisms incytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity.Pharmacogenomics J 11:121–129.

Li AP and Schlicht KE (2014) Application of a higher throughput approach to deriveapparent Michaelis-Menten constants of isoform-selective p450-mediated bio-transformation reactions in human hepatocytes. Drug Metab Lett 8:2–11.

Li G, Huang K, Nikolic D, and van Breemen RB (2015) High-throughput cytochromeP450 cocktail inhibition assay for assessing drug-drug and drug-botanical inter-actions. Drug Metab Dispos 43:1670–1678 10.1124/dmd.115.065987.

Li L, Tu M, Yang X, Sun S, Wu X, Zhou H, Zeng S, and Jiang H (2014b) Thecontribution of human OCT1, OCT3, and CYP3A4 to nitidine chloride-inducedhepatocellular toxicity. Drug Metab Dispos 42:1227–1234.

Li X, Jeso V, Heyward S, Walker GS, Sharma R, Micalizio GC, and Cameron MD(2014a) Characterization of T-5 N-oxide formation as the first highly selectivemeasure of CYP3A5 activity. Drug Metab Dispos 42:334–342.

Li XQ, Björkman A, Andersson TB, Ridderström M, and Masimirembwa CM (2002)Amodiaquine clearance and its metabolism to N-desethylamodiaquine is mediatedby CYP2C8: a new high affinity and turnover enzyme-specific probe substrate. JPharmacol Exp Ther 300:399–407.

Li Y, Zhou D, Ferguson SS, Dorff P, Simpson TR, and Grimm SW (2010) In vitroassessment of metabolic drug–drug interaction potential of AZD2624, neurokinin-3receptor antagonist, through cytochrome P(450) enzyme identification, inhibition,and induction studies. Xenobiotica 40:721–729.

Lilja JJ, Backman JT, and Neuvonen PJ (2005) Effect of gemfibrozil on the phar-macokinetics and pharmacodynamics of racemic warfarin in healthy subjects. Br JClin Pharmacol 59:433–439.

Lin JH and Lu AY (1998) Inhibition and induction of cytochrome P450 and theclinical implications. Clin Pharmacokinet 35:361–390.

Ling J, Johnson KA, Miao Z, Rakhit A, Pantze MP, Hamilton M, Lum BL,and Prakash C (2006) Metabolism and excretion of erlotinib, a small moleculeinhibitor of epidermal growth factor receptor tyrosine kinase, in healthy malevolunteers. Drug Metab Dispos 34:420–426.

Linnet K and Olesen OV (1997) Metabolism of clozapine by cDNA-expressed humancytochrome P450 enzymes. Drug Metab Dispos 25:1379–1382.

Liu D, Gao Y, Wang H, Zi J, Huang H, Ji J, Zhou R, Nan Y, Wang S, and Zheng X(2010a) Evaluation of the effects of cytochrome P450 nonsynonymous single-

nucleotide polymorphisms on tanshinol borneol ester metabolism and inhibitionpotential. Drug Metab Dispos 38:2259–2265.

Liu D, Zheng X, Tang Y, Zi J, Nan Y, Wang S, Xiao C, Zhu J, and Chen C (2010b)Metabolism of tanshinol borneol ester in rat and human liver microsomes. DrugMetab Dispos 38:1464–1470.

Liu K, Li F, Lu J, Liu S, Dorko K, Xie W, and Ma X (2014) Bedaquiline metabolism:enzymes and novel metabolites. Drug Metab Dispos 42:863–866.

Lopez Garcia MP, Dansette PM, Valadon P, Amar C, Beaune PH, Guengerich FP,and Mansuy D (1993) Human-liver cytochromes P-450 expressed in yeast as toolsfor reactive-metabolite formation studies. Oxidative activation of tienilic acid bycytochromes P-450 2C9 and 2C10. Eur J Biochem 213:223–232.

López-Rodríguez R, Novalbos J, Gallego-Sandín S, Román-Martínez M, Torrado J,Gisbert JP, and Abad-Santos F (2008) Influence of CYP2C8 and CYP2C9 poly-morphisms on pharmacokinetic and pharmacodynamic parameters of racemic andenantiomeric forms of ibuprofen in healthy volunteers. Pharmacol Res 58:77–84.

LoRusso PM, Piha-Paul SA, Mita M, Colevas AD, Malhi V, Colburn D, Yin M, LowJA, and Graham RA (2013) Co-administration of vismodegib with rosiglitazone orcombined oral contraceptive in patients with locally advanced or metastatic solidtumors: a pharmacokinetic assessment of drug-drug interaction potential. CancerChemother Pharmacol 71:193–202.

Lu C, Suri A, and Shimoga P (2012) Application of physiologically based pharma-cokinetic modeling and simulation for waiver of orteronel drug-drug interactiontrials, in 12th European ISS Meeting; Noordwijk, Netherlands (June 17-21, 2012).Available from: http://issx.confex.com/issx/12euro/webprogram/Paper27322.html(Accessed June 18, 2015).

Lundblad MS, Stark K, Eliasson E, Oliw E, and Rane A (2005) Biosynthesis ofepoxyeicosatrienoic acids varies between polymorphic CYP2C enzymes. BiochemBiophys Res Commun 327:1052–1057.

Ma B, Subramanian R, Schrag ML, Rodrigues AD, and Tang C (2004) CytochromeP450 2C8 (CYP2C8)-mediated hydroxylation of an endothelin ETA receptor an-tagonist in human liver microsomes. Drug Metab Dispos 32:473–478.

Macé K, Bowman ED, Vautravers P, Shields PG, Harris CC, and Pfeifer AM (1998)Characterisation of xenobiotic-metabolising enzyme expression in human bron-chial mucosa and peripheral lung tissues. Eur J Cancer 34:914–920.

Mach CM, Chen JH, Mosley SA, Kurzrock R, and Smith JA (2010) Evaluation ofliposomal curcumin cytochrome p450 metabolism. Anticancer Res 30:811–814.

Madan A, Fisher A, Jin L, Chapman D, and Bozigian HP (2007) In vitro metabolism ofindiplon and an assessment of its drug interaction potential. Xenobiotica 37:736–752.

Madan A, Graham RA, Carroll KM, Mudra DR, Burton LA, Krueger LA, Downey AD,Czerwinski M, Forster J, and Ribadeneira MD (2003) Effects of prototypical mi-crosomal enzyme inducers on cytochrome P450 expression in cultured human he-patocytes. Drug Metab Dispos 31:421–431.

Makishima M, Lu TT, Xie W, Whitfield GK, Domoto H, Evans RM, Haussler MR,and Mangelsdorf DJ (2002) Vitamin D receptor as an intestinal bile acid sensor.Science 296:1313–1316.

Mancy A, Antignac M, Minoletti C, Dijols S, Mouries V, Duong NT, Battioni P,Dansette PM, and Mansuy D (1999) Diclofenac and its derivatives as tools forstudying human cytochromes P450 active sites: particular efficiency and regiose-lectivity of P450 2Cs. Biochemistry 38:14264–14270.

Mancy A, Dijols S, Poli S, Guengerich P, and Mansuy D (1996) Interaction of sulfa-phenazole derivatives with human liver cytochromes P450 2C: molecular origin ofthe specific inhibitory effects of sulfaphenazole on CYP 2C9 and consequences forthe substrate binding site topology of CYP 2C9. Biochemistry 35:16205–16212.

Mano Y, Usui T, and Kamimura H (2007) The UDP-glucuronosyltransferase 2B7isozyme is responsible for gemfibrozil glucuronidation in the human liver. DrugMetab Dispos 35:2040–2044.

Marill J, Capron CC, Idres N, and Chabot GG (2002) Human cytochrome P450sinvolved in the metabolism of 9-cis- and 13-cis-retinoic acids. Biochem Pharmacol63:933–943.

Marill J, Cresteil T, Lanotte M, and Chabot GG (2000) Identification of human cy-tochrome P450s involved in the formation of all-trans-retinoic acid principal me-tabolites. Mol Pharmacol 58:1341–1348.

Marill J, Idres N, Capron CC, Nguyen E, and Chabot GG (2003) Retinoic acid me-tabolism and mechanism of action: a review. Curr Drug Metab 4:1–10.

Martínez C, García-Martín E, Blanco G, Gamito FJ, Ladero JM, and Agúndez JA(2005) The effect of the cytochrome P450 CYP2C8 polymorphism on the dispositionof (R)-ibuprofen enantiomer in healthy subjects. Br J Clin Pharmacol 59:62–69.

Martis S, Peter I, Hulot JS, Kornreich R, Desnick RJ, and Scott SA (2013) Multi-ethnic distribution of clinically relevant CYP2C genotypes and haplotypes. Phar-macogenomics J 13:369–377.

Marwa KJ, Schmidt T, Sjögren M, Minzi OM, Kamugisha E, and Swedberg G (2014) Cy-tochrome P450 single nucleotide polymorphisms in an indigenous Tanzanian population:a concern about the metabolism of artemisinin-based combinations. Malar J 13:420.

Masek V, Anzenbacherová E, Etrych T, Strohalm J, Ulbrich K, and Anzenbacher P(2011) Interaction of N-(2-hydroxypropyl)methacrylamide copolymer-doxorubicinconjugates with human liver microsomal cytochromes P450: comparison with freedoxorubicin. Drug Metab Dispos 39:1704–1710.

Masimirembwa CM, Otter C, Berg M, Jönsson M, Leidvik B, Jonsson E, Johansson T,Bäckman A, Edlund A, and Andersson TB (1999) Heterologous expression andkinetic characterization of human cytochromes P-450: validation of a pharmaceu-tical tool for drug metabolism research. Drug Metab Dispos 27:1117–1122.

McClue SJ and Stuart I (2008) Metabolism of the trisubstituted purine cyclin-dependent kinase inhibitor seliciclib (R-roscovitine) in vitro and in vivo. DrugMetab Dispos 36:561–570.

McFayden MC, Melvin WT, and Murray GI (1998) Regional distribution of individualforms of cytochrome P450 mRNA in normal adult human brain. Biochem Phar-macol 55:825–830.

McLaren W, Pritchard B, Rios D, Chen Y, Flicek P, and Cunningham F (2010) De-riving the consequences of genomic variants with the Ensembl API and SNP EffectPredictor. Bioinformatics 26:2069–2070.


http://issx.confex.com/issx/12euro/webprogram/Paper27322.html

Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, AntmanEM, Macias W, and Braunwald E (2009) Cytochrome p-450 polymorphisms andresponse to clopidogrel. N Engl J Med 360:354–362.

Melet A, Marques-Soares C, Schoch GA, Macherey AC, Jaouen M, Dansette PM, SariMA, Johnson EF, and Mansuy D (2004) Analysis of human cytochrome P450 2C8substrate specificity using a substrate pharmacophore and site-directed mutants.Biochemistry 43:15379–15392.

Menon RM, Badri PS, Wang T, Polepally AR, Zha J, Khatri A, Wang H, Hu B,Coakley EP, and Podsadecki TJ (2015) Drug-drug interaction profile of the all-oralanti-hepatitis C virus regimen of paritaprevir/ritonavir, ombitasvir, and dasabuvir.J Hepatol 63:20–29.

Miller VP, Stresser DM, Blanchard AP, Turner S, and Crespi CL (2000) Fluorometrichigh-throughput screening for inhibitors of cytochrome P450. Ann N Y Acad Sci919:26–32.

Miners JO, Coulter S, Birkett DJ, and Goldstein JA (2000) Torsemide metabolism byCYP2C9 variants and other human CYP2C subfamily enzymes. Pharmacogenetics10:267–270.

Minhas S, Setia N, Pandita S, Saxena R, Verma IC, and Aggarwal S (2013) Preva-lence of CYP2C8 polymorphisms in a North Indian population. Genet Mol Res 12:2260–2266.

Misaka S, Kawabe K, Onoue S, Werba JP, Giroli M, Tamaki S, Kan T, Kimura J,Watanabe H, and Yamada S (2013) Effects of green tea catechins on cytochromeP450 2B6, 2C8, 2C19, 2D6 and 3A activities in human liver and intestinal mi-crosomes. Drug Metab Pharmacokinet 28:244–249.

Miyazawa M, Shindo M, and Shimada T (2002) Sex differences in the metabolism of(+)- and (-)-limonene enantiomers to carveol and perillyl alcohol derivatives bycytochrome p450 enzymes in rat liver microsomes. Chem Res Toxicol 15:15–20.

Mizuno Y, Tani N, Komuro S, Kanamaru H, and Nakatsuka I (2003) In vitro me-tabolism of perospirone in rat, monkey and human liver microsomes. Eur J DrugMetab Pharmacokinet 28:59–65.

Moller RA, Fisher JM, Taylor AE, Kolluri S, Gardner MJ, Obach RS, and Walsky RL(2006) Effects of steady-state lasofoxifene on CYP2D6- and CYP2E1-mediatedmetabolism. Ann Pharmacother 40:32–37.

Monsarrat B, Royer I, Wright M, and Cresteil T (1997) Biotransformation of taxoidsby human cytochromes P450: structure-activity relationship. Bull Cancer 84:125–133.

Moody DE, Slawson MH, Strain EC, Laycock JD, Spanbauer AC, and Foltz RL (2002)A liquid chromatographic-electrospray ionization-tandem mass spectrometricmethod for determination of buprenorphine, its metabolite, norbuprenorphine, anda coformulant, naloxone, that is suitable for in vivo and in vitro metabolismstudies. Anal Biochem 306:31–39.

Moon Y, Kim SY, Ji HY, Kim YK, Chae HJ, Chae SW, and Lee HS (2007) Charac-terization of cytochrome P450s mediating ipriflavone metabolism in human livermicrosomes. Xenobiotica 37:246–259.

Morioka Y, Otsu M, Naito S, and Imai T (2002) Phosphonate O-deethylation of [4-(4-bromo-2-cyano-phenylcarbamoyl) benzyl]-phosphonic acid diethyl ester, a lipopro-tein lipase-promoting agent, catalyzed by cytochrome P450 2C8 and 3A4 in humanliver microsomes. Drug Metab Dispos 30:301–306.

Mount DL, Patchen LC, Nguyen-Dinh P, Barber AM, Schwartz IK, and Churchill FC(1986) Sensitive analysis of blood for amodiaquine and three metabolites by high-performance liquid chromatography with electrochemical detection. J ChromatogrA 383:375–386.

Mukai Y, Toda T, Hayakawa T, Eliasson E, Rane A, and Inotsume N (2014) Losartancompetitively inhibits CYP2C8-dependent paclitaxel metabolism in vitro. BiolPharm Bull 37:1550–1554.

Mukkavilli R, Gundala SR, Yang C, Donthamsetty S, Cantuaria G, Jadhav GR,Vangala S, Reid MD, and Aneja R (2014) Modulation of cytochrome P450 metab-olism and transport across intestinal epithelial barrier by ginger biophenolics.PLoS One 9:e108386.

Mukoyoshi M, Nishimura S, Hoshide S, Umeda S, Kanou M, Taniguchi K,and Muroga H (2008) In vitro drug-drug interaction studies with febuxostat, anovel non-purine selective inhibitor of xanthine oxidase: plasma protein binding,identification of metabolic enzymes and cytochrome P450 inhibition. Xenobiotica38:496–510.

Mürdter TE, Kerb R, Turpeinen M, Schroth W, Ganchev B, Böhmer GM, Igel S,Schaeffeler E, Zanger U, and Brauch H (2012) Genetic polymorphism of cyto-chrome P450 2D6 determines oestrogen receptor activity of the major infertilitydrug clomiphene via its active metabolites. Hum Mol Genet 21:1145–1154.

Muschler E, Lal J, Jetter A, Rattay A, Zanger U, Zadoyan G, Fuhr U,and Kirchheiner J (2009) The role of human CYP2C8 and CYP2C9 variants inpioglitazone metabolism in vitro. Basic Clin Pharmacol Toxicol 105:374–379.

Muthiah YD, Lee WL, Teh LK, Ong CE, and Ismail R (2005) Genetic polymorphism ofCYP2C8 in three Malaysian ethnics: CYP2C8*2 and CYP2C8*3 are found inMalaysian Indians. J Clin Pharm Ther 30:487–490.

Muthiah YD, Ong CE, Sulaiman SA, Tan SC, and Ismail R (2012) In-vitro inhibitoryeffect of Tualang honey on cytochrome P450 2C8 activity. J Pharm Pharmacol 64:1761–1769.

Mück W (1998) Rational assessment of the interaction profile of cerivastatin supportsits low propensity for drug interactions. Drugs 56 (Suppl 1):15–23, discussion 33.

Mück W (2000) Clinical pharmacokinetics of cerivastatin. Clin Pharmacokinet 39:99–116.

Mück W, Ochmann K, Rohde G, Unger S, and Kuhlmann J (1998) Influence oferythromycin pre- and co-treatment on single-dose pharmacokinetics of the HMG-CoA reductase inhibitor cerivastatin. Eur J Clin Pharmacol 53:469–473.

Nadin L and Murray M (1999) Participation of CYP2C8 in retinoic acid 4-hydroxylationin human hepatic microsomes. Biochem Pharmacol 58:1201–1208.

Naik H, Wu JT, Palmer R, and McLean L (2012) The effects of febuxostat on thepharmacokinetic parameters of rosiglitazone, a CYP2C8 substrate. Br J ClinPharmacol 74:327–335.

Nakagomi-Hagihara R, Nakai D, and Tokui T (2007) Inhibition of human organicanion transporter 3 mediated pravastatin transport by gemfibrozil and the me-tabolites in humans. Xenobiotica 37:416–426.

Nakajima M, Fujiki Y, Noda K, Ohtsuka H, Ohkuni H, Kyo S, Inoue M, Kuroiwa Y,and Yokoi T (2003) Genetic polymorphisms of CYP2C8 in Japanese population.Drug Metab Dispos 31:687–690.

Nakamura K, Ariyoshi N, Iwatsubo T, Fukunaga Y, Higuchi S, Itoh K, Shimada N,Nagashima K, Yokoi T, and Yamamoto K (2005) Inhibitory effects of nicardipine tocytochrome P450 (CYP) in human liver microsomes. Biol Pharm Bull 28:882–885.

Naraharisetti SB, Lin YS, Rieder MJ, Marciante KD, Psaty BM, Thummel KE,and Totah RA (2010) Human liver expression of CYP2C8: gender, age, and geno-type effects. Drug Metab Dispos 38:889–893.

Narimatsu S, Yonemoto R, Saito K, Takaya K, Kumamoto T, Ishikawa T, AsanumaM, Funada M, Kiryu K, and Naito S (2006) Oxidative metabolism of 5-methoxy-N,N-diisopropyltryptamine (Foxy) by human liver microsomes and recombinant cy-tochrome P450 enzymes. Biochem Pharmacol 71:1377–1385.

Nassar AE, King I, Paris BL, Haupt L, Ndikum-Moffor F, Campbell R, Usuki E,Skibbe J, Brobst D, and Ogilvie BW (2009) An in vitro evaluation of the victim andperpetrator potential of the anticancer agent laromustine (VNP40101M), based onreaction phenotyping and inhibition and induction of cytochrome P450 enzymes.Drug Metab Dispos 37:1922–1930.

Nebot N, Crettol S, d’Esposito F, Tattam B, Hibbs DE, and Murray M (2010) Par-ticipation of CYP2C8 and CYP3A4 in the N-demethylation of imatinib in humanhepatic microsomes. Br J Pharmacol 161:1059–1069.

Negishi I, Tsuda-Tsukimoto M, Kozakai K, and Kume T (2007) Utility of cryopreservedhuman hepatocytes for assessment of mechanism-based inactivation, in 8th In-ternational ISXX Meeting; Sendai, Japan (October 9-12, 2007). Available from: http://issx.confex.com/issx/intl8/webprogram/Paper6588.html (Accessed June 18, 2015).

Neuvonen PJ (2010) Drug interactions with HMG-CoA reductase inhibitors (statins):the importance of CYP enzymes, transporters and pharmacogenetics. Curr OpinInvestig Drugs 11:323–332.

Neuvonen PJ (2012) Towards safer and more predictable drug treatment–reflectionsfrom studies of the First BCPT Prize awardee. Basic Clin Pharmacol Toxicol 110:207–218.

Neuvonen PJ, Niemi M, and Backman JT (2006) Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther 80:565–581.

Nguyen L, Holland J, Miles D, Engel C, Benrimoh N, O’Reilly T, and Lacy S (2015)Pharmacokinetic (PK) drug interaction studies of cabozantinib: Effect of CYP3Ainducer rifampin and inhibitor ketoconazole on cabozantinib plasma PK and effectof cabozantinib on CYP2C8 probe substrate rosiglitazone plasma PK. J ClinPharmacol 55:1012–1023.

Nicolas JM, Chanteux H, Rosa M, Watanabe S, and Stockis A (2012) Effect of gem-fibrozil on the metabolism of brivaracetam in vitro and in human subjects. DrugMetab Dispos 40:1466–1472.

Niemi M, Backman JT, Granfors M, Laitila J, Neuvonen M, and Neuvonen PJ(2003a) Gemfibrozil considerably increases the plasma concentrations of rosigli-tazone. Diabetologia 46:1319–1323.

Niemi M, Backman JT, Juntti-Patinen L, Neuvonen M, and Neuvonen PJ (2005a)Coadministration of gemfibrozil and itraconazole has only a minor effect on thepharmacokinetics of the CYP2C9 and CYP3A4 substrate nateglinide. Br J ClinPharmacol 60:208–217.

Niemi M, Backman JT, Kajosaari LI, Leathart JB, Neuvonen M, Daly AK, EichelbaumM, Kivistö KT, and Neuvonen PJ (2005b) Polymorphic organic anion transportingpolypeptide 1B1 is a major determinant of repaglinide pharmacokinetics. ClinPharmacol Ther 77:468–478.

Niemi M, Backman JT, Neuvonen M, and Neuvonen PJ (2003b) Effects of gemfi-brozil, itraconazole, and their combination on the pharmacokinetics and pharma-codynamics of repaglinide: potentially hazardous interaction between gemfibroziland repaglinide. Diabetologia 46:347–351.

Niemi M, Backman JT, Neuvonen M, Neuvonen PJ, and Kivistö KT (2000) Rifampindecreases the plasma concentrations and effects of repaglinide. Clin PharmacolTher 68:495–500.

Niemi M, Backman JT, and Neuvonen PJ (2004a) Effects of trimethoprim and ri-fampin on the pharmacokinetics of the cytochrome P450 2C8 substrate rosiglita-zone. Clin Pharmacol Ther 76:239–249.

Niemi M, Kajosaari LI, Neuvonen M, Backman JT, and Neuvonen PJ (2004b) TheCYP2C8 inhibitor trimethoprim increases the plasma concentrations of repagli-nide in healthy subjects. Br J Clin Pharmacol 57:441–447.

Niemi M, Leathart JB, Neuvonen M, Backman JT, Daly AK, and Neuvonen PJ(2003c) Polymorphism in CYP2C8 is associated with reduced plasma concentra-tions of repaglinide. Clin Pharmacol Ther 74:380–387.

Niemi M, Neuvonen PJ, and Kivistö KT (2001) Effect of gemfibrozil on the pharmacoki-netics and pharmacodynamics of glimepiride. Clin Pharmacol Ther 70:439–445.

Niemi M, Pasanen MK, and Neuvonen PJ (2011) Organic anion transporting poly-peptide 1B1: a genetically polymorphic transporter of major importance for hepaticdrug uptake. Pharmacol Rev 63:157–181.

Niemi M, Tornio A, Pasanen MK, Fredrikson H, Neuvonen PJ, and Backman JT(2006) Itraconazole, gemfibrozil and their combination markedly raise the plasmaconcentrations of loperamide. Eur J Clin Pharmacol 62:463–472.

Nirogi R, Kandikere V, Palacharla RC, Bhyrapuneni G, Kanamarlapudi VB,Ponnamaneni RK, and Manoharan AK (2014) Identification of a suitable and selec-tive inhibitor towards aldehyde oxidase catalyzed reactions. Xenobiotica 44:197–204.

Nirogi R, Palacharla RC, Uthukam V, Manoharan A, Srikakolapu SR, KalaikadhibanI, Boggavarapu RK, Ponnamaneni RK, Ajjala DR, and Bhyrapuneni G (2015)Chemical inhibitors of CYP450 enzymes in liver microsomes: combining selectivityand unbound fractions to guide selection of appropriate concentration in pheno-typing assays. Xenobiotica 45:95–106.

Nishihara M, Sudo M, Kawaguchi N, Takahashi J, Kiyota Y, Kondo T, and Asahi S(2012) An unusual metabolic pathway of sipoglitazar, a novel antidiabetic agent:

236 Backman et al.



cytochrome P450-catalyzed oxidation of sipoglitazar acyl glucuronide. Drug MetabDispos 40:249–258.

Nishimura M, Yaguti H, Yoshitsugu H, Naito S, and Satoh T (2003) Tissue distri-bution of mRNA expression of human cytochrome P450 isoforms assessed by high-sensitivity real-time reverse transcription PCR. Yakugaku Zasshi 123:369–375.

Nishimura M, Yoshitsugu H, Naito S, and Hiraoka I (2002) Evaluation of gene in-duction of drug-metabolizing enzymes and transporters in primary culture of hu-man hepatocytes using high-sensitivity real-time reverse transcription PCR.Yakugaku Zasshi 122:339–361.

Nishiya Y, Hagihara K, Kurihara A, Okudaira N, Farid NA, Okazaki O, and Ikeda T(2009) Comparison of mechanism-based inhibition of human cytochrome P4502C19 by ticlopidine, clopidogrel, and prasugrel. Xenobiotica 39:836–843.

Niwa T, Sato R, Yabusaki Y, Ishibashi F, and Katagiri M (1999) Contribution ofhuman hepatic cytochrome P450s and steroidogenic CYP17 to the N-demethylationof aminopyrine. Xenobiotica 29:187–193.

Niwa T, Tsutsui M, Kishimoto K, Yabusaki Y, Ishibashi F, and Katagiri M (2000)Inhibition of drug-metabolizing enzyme activity in human hepatic cytochromeP450s by bisphenol A. Biol Pharm Bull 23:498–501.

Obach RS (2000) Inhibition of human cytochrome P450 enzymes by constituents ofSt. John’s Wort, an herbal preparation used in the treatment of depression. JPharmacol Exp Ther 294:88–95.

Obach RS, Walsky RL, and Venkatakrishnan K (2007) Mechanism-based in-activation of human cytochrome p450 enzymes and the prediction of drug-druginteractions. Drug Metab Dispos 35:246–255.

O’Donnell CJ, Grime K, Courtney P, Slee D, and Riley RJ (2007) The development ofa cocktail CYP2B6, CYP2C8, and CYP3A5 inhibition assay and a preliminaryassessment of utility in a drug discovery setting. Drug Metab Dispos 35:381–385.

Ogilvie BW, Zhang D, Li W, Rodrigues AD, Gipson AE, Holsapple J, Toren P,and Parkinson A (2006) Glucuronidation converts gemfibrozil to a potent,metabolism-dependent inhibitor of CYP2C8: implications for drug-drug interac-tions. Drug Metab Dispos 34:191–197.

Ohtsuki S, Schaefer O, Kawakami H, Inoue T, Liehner S, Saito A, Ishiguro N, KishimotoW, Ludwig-Schwellinger E, and Ebner T (2012) Simultaneous absolute protein quan-tification of transporters, cytochromes P450, and UDP-glucuronosyltransferases as anovel approach for the characterization of individual human liver: comparisonwith mRNA levels and activities. Drug Metab Dispos 40:83–92.

Ohyama K, Nakajima M, Nakamura S, Shimada N, Yamazaki H, and Yokoi T (2000)A significant role of human cytochrome P450 2C8 in amiodarone N-deethylation:an approach to predict the contribution with relative activity factor. Drug MetabDispos 28:1303–1310.

Olesen OV and Linnet K (2000) Identification of the human cytochrome P450 iso-forms mediating in vitro N-dealkylation of perphenazine. Br J Clin Pharmacol 50:563–571.

Ong CE, Coulter S, Birkett DJ, Bhasker CR, and Miners JO (2000) The xenobioticinhibitor profile of cytochrome P4502C8. Br J Clin Pharmacol 50:573–580.

Paganotti GM, Cosentino V, Russo G, Tabacchi F, Gramolelli S, Coluzzi M,and Romano R (2014) Absence of the human CYP2C8*3 allele in Ugandan childrenexposed to Plasmodium falciparum malaria. Infect Genet Evol 27:432–435.

Paganotti GM, Gallo BC, Verra F, Sirima BS, Nebié I, Diarra A, Coluzzi M,and Modiano D (2011) Human genetic variation is associated with Plasmodiumfalciparum drug resistance. J Infect Dis 204:1772–1778.

Paganotti GM, Gramolelli S, Tabacchi F, Russo G, Modiano D, Coluzzi M,and Romano R (2012) Distribution of human CYP2C8*2 allele in three differentAfrican populations. Malar J 11:125.

Pan Y, Tiong KH, Abd-Rashid BA, Ismail Z, Ismail R, Mak JW, and Ong CE (2012)Inhibitory effects of cytochrome P450 enzymes CYP2C8, CYP2C9, CYP2C19 andCYP3A4 by Labisia pumila extracts. J Ethnopharmacol 143:586–591.

Pan Y, Tiong KH, Abd-Rashid BA, Ismail Z, Ismail R, Mak JW, and Ong CE (2014)Effect of eurycomanone on cytochrome P450 isoforms CYP1A2, CYP2A6, CYP2C8,CYP2C9, CYP2C19, CYP2E1 and CYP3A4 in vitro. J Nat Med 68:402–406.

Pang CY, Mak JW, Ismail R, and Ong CE (2012) In vitro modulatory effects offlavonoids on human cytochrome P450 2C8 (CYP2C8). Naunyn SchmiedebergsArch Pharmacol 385:495–502.

Parikh S, Ouedraogo JB, Goldstein JA, Rosenthal PJ, and Kroetz DL (2007) Amo-diaquine metabolism is impaired by common polymorphisms in CYP2C8: impli-cations for malaria treatment in Africa. Clin Pharmacol Ther 82:197–203.

Paris BL, Ogilvie BW, Scheinkoenig JA, Ndikum-Moffor F, Gibson R, and ParkinsonA (2009) In vitro inhibition and induction of human liver cytochrome p450 enzymesby milnacipran. Drug Metab Dispos 37:2045–2054.

Park JY, Kim KA, Kang MH, Kim SL, and Shin JG (2004) Effect of rifampin on thepharmacokinetics of rosiglitazone in healthy subjects. Clin Pharmacol Ther 75:157–162.

Parte P and Kupfer D (2005) Oxidation of tamoxifen by human flavin-containingmonooxygenase (FMO) 1 and FMO3 to tamoxifen-N-oxide and its novel reductionback to tamoxifen by human cytochromes P450 and hemoglobin. Drug MetabDispos 33:1446–1452.

Pearce RE, Gotschall RR, Kearns GL, and Leeder JS (2001) Cytochrome P450 in-volvement in the biotransformation of cisapride and racemic norcisapride in vitro:differential activity of individual human CYP3A isoforms. Drug Metab Dispos 29:1548–1554.

Pechandova K, Buzkova H, Matouskova O, Perlik F, and Slanar O (2012) Geneticpolymorphisms of CYP2C8 in the Czech Republic. Genet Test Mol Biomarkers 16:812–816.

Pelkonen O (2015) Drug Metabolism - From In Vitro to In Vivo, From Simple toComplex: Reflections of the BCPT Nordic Prize 2014 Awardee. Basic Clin Phar-macol Toxicol 117:147–155.

Pelkonen O, Myllynen P, Taavitsainen P, Boobis AR, Watts P, Lake BG, Price RJ,Renwick AB, Gómez-Lechón MJ, and Castell JV (2001) Carbamazepine: a ‘blind’assessment of CVP-associated metabolism and interactions in human liver-derivedin vitro systems. Xenobiotica 31:321–343.

Pelkonen O, Turpeinen M, Hakkola J, Honkakoski P, Hukkanen J, and Raunio H(2008) Inhibition and induction of human cytochrome P450 enzymes: current sta-tus. Arch Toxicol 82:667–715.

Peng Y, Wu H, Zhang X, Zhang F, Qi H, Zhong Y, Wang Y, Sang H, Wang G, and SunJ (2015) A comprehensive assay for nine major cytochrome P450 enzymes activitieswith 16 probe reactions on human liver microsomes by a single LC/MS/MS run tosupport reliable in vitro inhibitory drug-drug interaction evaluation. Xenobiotica45:961–977.

Perez-Ruixo JJ, Piotrovskij V, Zhang S, Hayes S, De Porre P, and Zannikos P (2006)Population pharmacokinetics of tipifarnib in healthy subjects and adult cancerpatients. Br J Clin Pharmacol 62:81–96.

Perloff ES, Mason AK, Dehal SS, Blanchard AP, Morgan L, Ho T, Dandeneau A,Crocker RM, Chandler CM, and Boily N (2009) Validation of cytochrome P450time-dependent inhibition assays: a two-time point IC50 shift approach facilitateskinact assay design. Xenobiotica 39:99–112.

Pichard L, Curi-Pedrosa R, Bonfils C, Jacqz-Aigrain E, Domergue J, Joyeux H,Cosme J, Guengerich FP, and Maurel P (1995) Oxidative metabolism of lanso-prazole by human liver cytochromes P450. Mol Pharmacol 47:410–418.

Picard N, Cresteil T, Djebli N, and Marquet P (2005) In vitro metabolism study ofbuprenorphine: evidence for new metabolic pathways. Drug Metab Dispos 33:689–695.

Picard N, Rouguieg-Malki K, Kamar N, Rostaing L, and Marquet P (2011) CYP3A5genotype does not influence everolimus in vitro metabolism and clinical pharma-cokinetics in renal transplant recipients. Transplantation 91:652–656.

Pimazoni A (2009) The impact of tuberculosis treatment on glycaemic control and thesignificant response to rosiglitazone. BMJ Case Rep 2009 10.1136/bcr.09.2008.0994.

PMDA (2014) Japanese Pharmaceuticals and Medical Devices Agency, review report:Acofide. Available from: http://www.pmda.go.jp/files/000153467.pdf (AccessedSeptember 15, 2015).

Polasek TM, Elliot DJ, Lewis BC, and Miners JO (2004) Mechanism-based in-activation of human cytochrome P4502C8 by drugs in vitro. J Pharmacol Exp Ther311:996–1007.

Porubsky PR, Meneely KM, and Scott EE (2008) Structures of human cytochromeP-450 2E1. Insights into the binding of inhibitors and both small molecular weightand fatty acid substrates. J Biol Chem 283:33698–33707.

Prakash C, Wang W, O’Connell T, and Johnson KA (2008) CYP2C8- and CYP3A-mediated C-demethylation of (3-[(4-tert-butylbenzyl)-(pyridine-3-sulfonyl)-amino]-methyl-phenoxy)-acetic acid (CP-533,536), an EP2 receptor-selective prostaglandinE2 agonist: characterization of metabolites by high-resolution liquid chromatography-tandem mass spectrometry and liquid chromatography/mass spectrometry-nuclearmagnetic resonance. Drug Metab Dispos 36:2093–2103.

Projean D, Baune B, Farinotti R, Flinois JP, Beaune P, Taburet AM, and Ducharme J(2003a) In vitro metabolism of chloroquine: identification of CYP2C8, CYP3A4, andCYP2D6 as the main isoforms catalyzing N-desethylchloroquine formation. DrugMetab Dispos 31:748–754.

Projean D, Morin PE, Tu TM, and Ducharme J (2003b) Identification of CYP3A4and CYP2C8 as the major cytochrome P450 s responsible for morphineN-demethylation in human liver microsomes. Xenobiotica 33:841–854.

Prueksaritanont T, Gorham LM, Ma B, Liu L, Yu X, Zhao JJ, Slaughter DE, ArisonBH, and Vyas KP (1997) In vitro metabolism of simvastatin in humans [SBT]identification of metabolizing enzymes and effect of the drug on hepatic P450s.Drug Metab Dispos 25:1191–1199.

Prueksaritanont T, Lu P, Gorham L, Sternfeld F, and Vyas KP (2000) Interspeciescomparison and role of human cytochrome P450 and flavin-containing mono-oxygenase in hepatic metabolism of L-775,606, a potent 5-HT(1D) receptor agonist.Xenobiotica 30:47–59.

Prueksaritanont T, Ma B, and Yu N (2003) The human hepatic metabolism of sim-vastatin hydroxy acid is mediated primarily by CYP3A, and not CYP2D6. Br J ClinPharmacol 56:120–124.

Prueksaritanont T, Richards KM, Qiu Y, Strong-Basalyga K, Miller A, Li C, Eisen-handler R, and Carlini EJ (2005) Comparative effects of fibrates on drug metab-olizing enzymes in human hepatocytes. Pharm Res 22:71–78.

Prueksaritanont T, Tang C, Qiu Y, Mu L, Subramanian R, and Lin JH (2002) Effectsof fibrates on metabolism of statins in human hepatocytes. Drug Metab Dispos 30:1280–1287.

Pusalkar S, Zhou X, Li Y, Liao M, Yang J, Chong S, Venkatakrishnan K, andChowdhury S (2014) Absorption, metabolism, and excretion of alisertib(MLN8237), an aurora A kinase inhibitor, in patients with advanced solid tumorsor lymphomas, in 19th North American ISSX/29th JSSX Meeting; San Francisco,CA (October 19-23, 2014). Available from: http://issx.confex.com/issx/19NA/webprogrampreliminary/Paper34303.html (Accessed August 26, 2015).

Qi XY, Liang SC, Ge GB, Liu Y, Dong PP, Zhang JW, Wang AX, Hou J, Zhu LL,and Yang L (2013) Inhibitory effects of sanguinarine on human liver cytochromeP450 enzymes. Food Chem Toxicol 56:392–397.

Qu YQ, Fang ZZ, Yang L, Gao ZM, Liang R, Zhu LL, Dong PP, Zhang YY, Ge GB,and Wang LM (2011) Reversible inhibition of four important human liver cyto-chrome P450 enzymes by diethylstilbestrol. Pharmazie 66:216–221.

Quintieri L, Palatini P, Moro S, and Floreani M (2011) Inhibition of cytochrome P4502C8-mediated drug metabolism by the flavonoid diosmetin. Drug Metab Pharma-cokinet 26:559–568.

Rae JM, Johnson MD, LippmanME, and Flockhart DA (2001) Rifampin is a selective,pleiotropic inducer of drug metabolism genes in human hepatocytes: studies withcDNA and oligonucleotide expression arrays. J Pharmacol Exp Ther 299:849–857.

Rahman A, Korzekwa KR, Grogan J, Gonzalez FJ, and Harris JW (1994) Selectivebiotransformation of taxol to 6 alpha-hydroxytaxol by human cytochrome P4502C8. Cancer Res 54:5543–5546.

Rana R, Chen Y, Ferguson SS, Kissling GE, Surapureddi S, and Goldstein JA (2010)Hepatocyte nuclear factor 4alpha regulates rifampicin-mediated induction ofCYP2C genes in primary cultures of human hepatocytes. Drug Metab Dispos 38:591–599.


http://www.pmda.go.jp/files/000153467.pdf

http://issx.confex.com/issx/19NA/webprogrampreliminary/Paper34303.html

http://issx.confex.com/issx/19NA/webprogrampreliminary/Paper34303.html

Raucy JL, Mueller L, Duan K, Allen SW, Strom S, and Lasker JM (2002) Expressionand induction of CYP2C P450 enzymes in primary cultures of human hepatocytes.J Pharmacol Exp Ther 302:475–482.

Relling MV, Aoyama T, Gonzalez FJ, and Meyer UA (1990) Tolbutamide andmephenytoin hydroxylation by human cytochrome P450s in the CYP2C subfamily.J Pharmacol Exp Ther 252:442–447.

Rettie AE, Wienkers LC, Gonzalez FJ, Trager WF, and Korzekwa KR (1994) Im-paired (S)-warfarin metabolism catalysed by the R144C allelic variant of CYP2C9.Pharmacogenetics 4:39–42.

Reyderman L, Kosoglou T, Statkevich P, Pember L, Boutros T, Maxwell SE, AffrimeM, and Batra V (2004) Assessment of a multiple-dose drug interaction betweenezetimibe, a novel selective cholesterol absorption inhibitor and gemfibrozil. Int JClin Pharmacol Ther 42:512–518.

Rifkind AB, Lee C, Chang TK, and Waxman DJ (1995) Arachidonic acid metabolismby human cytochrome P450s 2C8, 2C9, 2E1, and 1A2: regioselective oxygenationand evidence for a role for CYP2C enzymes in arachidonic acid epoxygenation inhuman liver microsomes. Arch Biochem Biophys 320:380–389.

Robert M, Salvà M, Segarra R, Pavesi M, Esbri R, Roberts D, and Golor G (2007) Theprokinetic cinitapride has no clinically relevant pharmacokinetic interaction andeffect on QT during coadministration with ketoconazole. Drug Metab Dispos 35:1149–1156.

Rochat B, Zoete V, Grosdidier A, von Grünigen S, Marull M, and Michielin O (2008)In vitro biotransformation of imatinib by the tumor expressed CYP1A1 andCYP1B1. Biopharm Drug Dispos 29:103–118.

Roco A, Quiñones L, Agúndez JA, García-Martín E, Squicciarini V, Miranda C, GarayJ, Farfán N, Saavedra I, and Cáceres D (2012) Frequencies of 23 functionallysignificant variant alleles related with metabolism of antineoplastic drugs in thechilean population: comparison with caucasian and asian populations. Front Genet3:229.

Rodrigues AD, Kukulka MJ, Roberts EM, Ouellet D, and Rodgers TR (1996)[O-methyl 14C]naproxen O-demethylase activity in human liver microsomes: evi-dence for the involvement of cytochrome P4501A2 and P4502C9/10. Drug MetabDispos 24:126–136.

Rong H, Maclin D, Yao L, Lin J, Yin D, and Xu H (2008) Mechanism-based inhibitionof human liver microsomal cytochrome P450 3A by a focal adhesion kinase (FAK)inhibitor PF-562,27, in 2nd Asian Pacific ISSX Meeting; Shanghai, China (May 11-13, 2008). Available from: http://issx.confex.com/issx/ap08/webprogram/start.html(Accessed August 25, 2015).

Rostami-Hodjegan A and Tucker GT (2007) Simulation and prediction of in vivo drugmetabolism in human populations from in vitro data. Nat Rev Drug Discov 6:140–148.

Roustit M, Blondel E, Villier C, Fonrose X, and Mallaret MP (2010) Symptomatichypoglycemia associated with trimethoprim/sulfamethoxazole and repaglinide in adiabetic patient. Ann Pharmacother 44:764–767.

Rowbotham SE, Boddy AV, Redfern CP, Veal GJ, and Daly AK (2010) Relevance ofnonsynonymous CYP2C8 polymorphisms to 13-cis retinoic acid and paclitaxelhydroxylation. Drug Metab Dispos 38:1261–1266.

Röwer S, Bienzle U, Weise A, Lambertz U, Forst T, Otchwemah RN, Pfützner A,and Mockenhaupt FP (2005) Short communication: high prevalence of the cyto-chrome P450 2C8*2 mutation in Northern Ghana. Trop Med Int Health 10:1271–1273.

Rowland P, Blaney FE, Smyth MG, Jones JJ, Leydon VR, Oxbrow AK, Lewis CJ,Tennant MG, Modi S, and Eggleston DS (2006) Crystal structure of human cyto-chrome P450 2D6. J Biol Chem 281:7614–7622.

Rowland Yeo K, Rostami Hodjegan A, and Tucker GT (2004) Abundance of cyto-chromes P450 in human liver: a meta-analysis. Br J Clin Pharmacol 57:687–688.

Sahi J, Black CB, Hamilton GA, Zheng X, Jolley S, Rose KA, Gilbert D, LeCluyse EL,and Sinz MW (2003) Comparative effects of thiazolidinediones on in vitro P450enzyme induction and inhibition. Drug Metab Dispos 31:439–446.

Sai Y, Dai R, Yang TJ, Krausz KW, Gonzalez FJ, Gelboin HV, and Shou M (2000)Assessment of specificity of eight chemical inhibitors using cDNA-expressed cyto-chromes P450. Xenobiotica 30:327–343.

Sakaeda T, Fujino H, Komoto C, Kakumoto M, Jin JS, Iwaki K, Nishiguchi K,Nakamura T, Okamura N, and Okumura K (2006) Effects of acid and lactone formsof eight HMG-CoA reductase inhibitors on CYP-mediated metabolism and MDR1-mediated transport. Pharm Res 23:506–512.

Säll C, Houston JB, and Galetin A (2012) A comprehensive assessment of repaglinidemetabolic pathways: impact of choice of in vitro system and relative enzyme con-tribution to in vitro clearance. Drug Metab Dispos 40:1279–1289.

Salminen KA, Meyer A, Jerabkova L, Korhonen LE, Rahnasto M, Juvonen RO,Imming P, and Raunio H (2011) Inhibition of human drug metabolizing cytochromeP450 enzymes by plant isoquinoline alkaloids. Phytomedicine 18:533–538.

Salonen JS, Nyman L, Boobis AR, Edwards RJ, Watts P, Lake BG, Price RJ, RenwickAB, Gómez-Lechón MJ, and Castell JV (2003) Comparative studies on the cyto-chrome p450-associated metabolism and interaction potential of selegiline betweenhuman liver-derived in vitro systems. Drug Metab Dispos 31:1093–1102.

Sane RS, Ramsden D, Sabo JP, Cooper C, Rowland L, Ting N, Whitcher-Johnstone A,and Tweedie DJ (2015) Contribution of major metabolites towards complex drug-drug interactions of deleobuvir: in vitro predictions and in vivo outcomes. DrugMetab Dispos pii: dmd.115.066985.

Sansen S, Yano JK, Reynald RL, Schoch GA, Griffin KJ, Stout CD, and Johnson EF(2007) Adaptations for the oxidation of polycyclic aromatic hydrocarbons exhibitedby the structure of human P450 1A2. J Biol Chem 282:14348–14355.

Sarasquete ME, García-Sanz R, Marín L, Alcoceba M, Chillón MC, BalanzateguiA, Santamaria C, Rosiñol L, de la Rubia J, and Hernandez MT (2008)Bisphosphonate-related osteonecrosis of the jaw is associated with polymorphismsof the cytochrome P450 CYP2C8 in multiple myeloma: a genome-wide single nu-cleotide polymorphism analysis. Blood 112:2709–2712.

Schelleman H, Han X, Brensinger CM, Quinney SK, Bilker WB, Flockhart DA, Li L,and Hennessy S (2014) Pharmacoepidemiologic and in vitro evaluation of potential

drug-drug interactions of sulfonylureas with fibrates and statins. Br J ClinPharmacol 78:639–648.

Schneck DW, Birmingham BK, Zalikowski JA, Mitchell PD, Wang Y, Martin PD,Lasseter KC, Brown CD, Windass AS, and Raza A (2004) The effect of gemfibrozilon the pharmacokinetics of rosuvastatin. Clin Pharmacol Ther 75:455–463.

Schoch GA, Yano JK, Sansen S, Dansette PM, Stout CD, and Johnson EF (2008)Determinants of cytochrome P450 2C8 substrate binding: structures of complexeswith montelukast, troglitazone, felodipine, and 9-cis-retinoic acid. J Biol Chem283:17227–17237.

Schoch GA, Yano JK, Wester MR, Griffin KJ, Stout CD, and Johnson EF (2004)Structure of human microsomal cytochrome P450 2C8. Evidence for a peripheralfatty acid binding site. J Biol Chem 279:9497–9503.

Scordo MG, Pengo V, Spina E, Dahl ML, Gusella M, and Padrini R (2002) Influence ofCYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose andmetabolic clearance. Clin Pharmacol Ther 72:702–710.

Schwartz JI, Stroh M, Gao B, Liu F, Rosko K, Zajic S, Meehan AJ, Ruckle J, Lai E,and Wagner JA (2009) Effects of laropiprant, a selective prostaglandin D(2) re-ceptor 1 antagonist, on the pharmacokinetics of rosiglitazone. Cardiovasc Ther 27:239–245.

Sevior DK, Hokkanen J, Tolonen A, Abass K, Tursas L, Pelkonen O, and Ahokas JT(2010) Rapid screening of commercially available herbal products for the inhibitionof major human hepatic cytochrome P450 enzymes using the N-in-one cocktail.Xenobiotica 40:245–254.

Shahabi P, Siest G, Meyer UA, and Visvikis-Siest S (2014) Human cytochrome P450epoxygenases: variability in expression and role in inflammation-related disorders.Pharmacol Ther 144:134–161.

Shimokawa Y, Yoda N, Kondo S, Yamamura Y, Takiguchi Y, and Umehara K (2015)Inhibitory Potential of Twenty Five Anti-tuberculosis Drugs on CYP Activities inHuman Liver Microsomes. Biol Pharm Bull 38:1425–1429 .

Shitara Y, Hirano M, Sato H, and Sugiyama Y (2004) Gemfibrozil and its glucuronideinhibit the organic anion transporting polypeptide 2 (OATP2/OATP1B1:SLC21A6)-mediated hepatic uptake and CYP2C8-mediated metabolism of cerivastatin:analysis of the mechanism of the clinically relevant drug-drug interaction betweencerivastatin and gemfibrozil. J Pharmacol Exp Ther 311:228–236.

Sidharta PN, Treiber A, and Dingemanse J (2015) Clinical pharmacokinetics andpharmacodynamics of the endothelin receptor antagonist macitentan. Clin Phar-macokinet 54:457–471.

Sim J, Choi E, Lee YM, Jeong GS, and Lee S (2015) In vitro inhibition of humancytochrome P450 by cudratricusxanthone A. Food Chem Toxicol 81:171–175.

Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Méneveau N, Steg PG,Ferrières J, Danchin N, and Becquemont L; French Registry of Acute ST-Elevationand Non-ST-Elevation Myocardial Infarction (FAST-MI) Investigators (2009) Ge-netic determinants of response to clopidogrel and cardiovascular events. N Engl JMed 360:363–375.

Singh R, Ting JG, Pan Y, Teh LK, Ismail R, and Ong CE (2008) Functional role ofIle264 in CYP2C8: mutations affect haem incorporation and catalytic activity.Drug Metab Pharmacokinet 23:165–174.

Sjögren E, Svanberg P, and Kanebratt KP (2012) Optimized experimental design forthe estimation of enzyme kinetic parameters: an experimental evaluation. DrugMetab Dispos 40:2273–2279.

Skerjanec A, Wang J, Maren K, and Rojkjaer L (2010) Investigation of the phar-macokinetic interactions of deferasirox, a once-daily oral iron chelator, with mid-azolam, rifampin, and repaglinide in healthy volunteers. J Clin Pharmacol 50:205–213.

Smith JA, Newman RA, Hausheer FH, and Madden T (2003) Evaluation of in vitrodrug interactions with karenitecin, a novel, highly lipophilic camptothecin de-rivative in phase II clinical development. J Clin Pharmacol 43:1008–1014.

Smith MT (2003) Mechanisms of troglitazone hepatotoxicity. Chem Res Toxicol 16:679–687.

Song M, Do H, Kwon OK, Yang EJ, Bae JS, Jeong TC, Song KS, and Lee S (2014a) AComparison of the In Vitro Inhibitory Effects of Thelephoric Acid and SKF-525A onHuman Cytochrome P450 Activity. Biomol Ther (Seoul) 22:155–160.

Song M, Hwang JY, Lee MY, Jee JG, Lee YM, Bae JS, Kim JA, Lee SH, and Lee S(2014b) In vitro inhibitory effect of piperlonguminine isolated from Piper longumon human cytochrome P450 1A2. Arch Pharm Res 37:1063–1068.

Sonnichsen DS, Liu Q, Schuetz EG, Schuetz JD, Pappo A, and Relling MV (1995)Variability in human cytochrome P450 paclitaxel metabolism. J Pharmacol ExpTher 275:566–575.

Soyama A, Hanioka N, Saito Y, Murayama N, Ando M, Ozawa S, and Sawada J(2002) Amiodarone N-deethylation by CYP2C8 and its variants, CYP2C8*3 andCYP2C8 P404A. Pharmacol Toxicol 91:174–178.

Soyama A, Saito Y, Hanioka N, Murayama N, Nakajima O, Katori N, Ishida S, Sai K,Ozawa S, and Sawada JI (2001) Non-synonymous single nucleotide alterationsfound in the CYP2C8 gene result in reduced in vitro paclitaxel metabolism. BiolPharm Bull 24:1427–1430.

Soyinka JO, Onyeji CO, Nathaniel TI, Odunfa OO, and Ebeshi BU (2013) Effects ofconcurrent administration of efavirenz on the disposition kinetics of amodiaquinein healthy volunteers. J Pharm Res 6:275–279.

Speed WC, Kang SP, Tuck DP, Harris LN, and Kidd KK (2009) Global variation inCYP2C8-CYP2C9 functional haplotypes. Pharmacogenomics J 9:283–290.

Spink DC, Eugster HP, Lincoln DW 2nd, Schuetz JD, Schuetz EG, Johnson JA,Kaminsky LS, and Gierthy JF (1992) 17 beta-estradiol hydroxylation catalyzed byhuman cytochrome P450 1A1: a comparison of the activities induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in MCF-7 cells with those from heterologous expres-sion of the cDNA. Arch Biochem Biophys 293:342–348.

Spink DC, Hayes CL, Young NR, Christou M, Sutter TR, Jefcoate CR, and Gierthy JF(1994) The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on estrogen metabolism inMCF-7 breast cancer cells: evidence for induction of a novel 17 beta-estradiol4-hydroxylase. J Steroid Biochem Mol Biol 51:251–258.

238 Backman et al.

http://issx.confex.com/issx/ap08/webprogram/start.html

Srivastava PK, Yun CH, Beaune PH, Ged C, and Guengerich FP (1991) Separation ofhuman liver microsomal tolbutamide hydroxylase and (S)-mephenytoin 49-hydroxylasecytochrome P-450 enzymes. Mol Pharmacol 40:69–79.

Staehli Hodel EM, Csajka C, Ariey F, Guidi M, Kabanywanyi AM, Duong S, Deco-sterd LA, Olliaro P, Beck HP, and Genton B (2013) Effect of single nucleotidepolymorphisms in cytochrome P450 isoenzyme and N-acetyltransferase 2 genes onthe metabolism of artemisinin-based combination therapies in malaria patientsfrom Cambodia and Tanzania. Antimicrob Agents Chemother 57:950–958.

Staffa JA, Chang J, and Green L (2002) Cerivastatin and reports of fatal rhabdo-myolysis. N Engl J Med 346:539–540.

Stage TB, Christensen MM, Feddersen S, Beck-Nielsen H, and Brøsen K (2013) Therole of genetic variants in CYP2C8, LPIN1, PPARGC1A and PPARg on the troughsteady-state plasma concentrations of rosiglitazone and on glycosylated haemo-globin A1c in type 2 diabetes. Pharmacogenet Genomics 23:219–227.

Störmer E, von Moltke LL, Shader RI, and Greenblatt DJ (2000) Metabolism of theantidepressant mirtazapine in vitro: contribution of cytochromes P-450 1A2, 2D6,and 3A4. Drug Metab Dispos 28:1168–1175.

Suarez-Kurtz G, Genro JP, de Moraes MO, Ojopi EB, Pena SD, Perini JA,Ribeiro-dos-Santos A, Romano-Silva MA, Santana I, and Struchiner CJ (2012)Global pharmacogenomics: Impact of population diversity on the distribution ofpolymorphisms in the CYP2C cluster among Brazilians. Pharmacogenomics J 12:267–276.

Such E, Cervera J, Terpos E, Bagán JV, Avaria A, Gómez I, Margaix M, Ibañez M,Luna I, and Cordón L (2011) CYP2C8 gene polymorphism and bisphosphonate-related osteonecrosis of the jaw in patients with multiple myeloma. Haematologica96:1557–1559.

Sun DX, Lu JC, Fang ZZ, Zhang YY, Cao YF, Mao YX, Zhu LL, Yin J, and Yang L(2010) Reversible inhibition of three important human liver cytochrome p450 en-zymes by tiliroside. Phytother Res 24:1670–1675.

Suttle AB, Grossmann KF, Ouellet D, Richards-Peterson LE, Aktan G, Gordon MS,LoRusso PM, Infante JR, Sharma S, and Kendra K (2015) Assessment of the druginteraction potential and single- and repeat-dose pharmacokinetics of the BRAFinhibitor dabrafenib. J Clin Pharmacol 55:392–400.

Sutton D, Butler AM, Nadin L, and Murray M (1997) Role of CYP3A4 in humanhepatic diltiazem N-demethylation: inhibition of CYP3A4 activity by oxidized dil-tiazem metabolites. J Pharmacol Exp Ther 282:294–300.

Suzuki A, Iida I, Tanaka F, Akimoto M, Fukushima K, Tani M, Ishizaki T, and ChibaK (1999) Identification of human cytochrome P-450 isoforms involved in metabo-lism of R(+)- and S(-)-gallopamil: utility of in vitro disappearance rate. Drug MetabDispos 27:1254–1259.

Synold TW, Dussault I, and Forman BM (2001) The orphan nuclear receptor SXRcoordinately regulates drug metabolism and efflux. Nat Med 7:584–590.

Tachibana S, Fujimaki Y, Yokoyama H, Okazaki O, and Sudo K (2005) In vitrometabolism of the calmodulin antagonist DY-9760e (3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidaz olylmethyl)-1H-indazole dihydro-chloride 3.5 hydrate) by human liver microsomes: involvement of cytochromes p450in atypical kinetics and potential drug interactions. Drug Metab Dispos 33:1628–1636.

Tamraz B, Fukushima H, Wolfe AR, Kaspera R, Totah RA, Floyd JS, Ma B, Chu C,Marciante KD, and Heckbert SR (2013) OATP1B1-related drug-drug and drug-gene interactions as potential risk factors for cerivastatin-induced rhabdomyolysis.Pharmacogenet Genomics 23:355–364.

Tan AR, Dowlati A, Stein MN, Jones SF, Infante JR, Bendell J, Kane MP, LevinsonKT, Suttle AB, and Burris HA 3rd (2014) Phase I study of weekly paclitaxel incombination with pazopanib and lapatinib in advanced solid malignancies. Br JCancer 110:2647–2654.

Tarkiainen EK, Holmberg MT, Tornio A, Neuvonen M, Neuvonen PJ, Backman JT,and Niemi M (2015) Carboxylesterase 1 c.428G.A single nucleotide variation in-creases the antiplatelet effects of clopidogrel by reducing its hydrolysis in humans.Clin Pharmacol Ther 97:650–658.

Teng WC, Oh JW, New LS, Wahlin MD, Nelson SD, Ho HK, and Chan EC (2010)Mechanism-based inactivation of cytochrome P450 3A4 by lapatinib. Mol Phar-macol 78:693–703.

TGA (2014) Australian Public Assessment Report for Crizotinib. Available from:https://www.tga.gov.au/file/882/download (Accessed September, 2015).

Thatcher JE, Zelter A, and Isoherranen N (2010) The relative importance of CYP26A1in hepatic clearance of all-trans retinoic acid. Biochem Pharmacol 80:903–912.

Thomas M, Bayha C, Vetter S, Hofmann U, Schwarz M, Zanger UM, and BraeuningA (2015) Activating and Inhibitory Functions of WNT/b-Catenin in the Induction ofCytochromes P450 by Nuclear Receptors in HepaRG Cells. Mol Pharmacol 87:1013–1020.

Thum T and Borlak J (2000) Gene expression in distinct regions of the heart. Lancet355:979–983.

Tomalik-Scharte D, Fuhr U, Hellmich M, Frank D, Doroshyenko O, Jetter A,and Stingl JC (2011) Effect of the CYP2C8 genotype on the pharmacokinetics andpharmacodynamics of repaglinide. Drug Metab Dispos 39:927–932.

Tornio A, Filppula AM, Kailari O, Neuvonen M, Nyrönen TH, Tapaninen T, NeuvonenPJ, Niemi M, and Backman JT (2014) Glucuronidation converts clopidogrel to astrong time-dependent inhibitor of CYP2C8: a phase II metabolite as a perpetrator ofdrug-drug interactions. Clin Pharmacol Ther 96:498–507.

Tornio A, Neuvonen PJ, and Backman JT (2006) The CYP2C8 inhibitor gemfibrozildoes not increase the plasma concentrations of zopiclone. Eur J Clin Pharmacol 62:645–651.

Tornio A, Niemi M, Neuvonen M, Laitila J, Kalliokoski A, Neuvonen PJ,and Backman JT (2008a) The effect of gemfibrozil on repaglinide pharmacokineticspersists for at least 12 h after the dose: evidence for mechanism-based inhibition ofCYP2C8 in vivo. Clin Pharmacol Ther 84:403–411.

Tornio A, Niemi M, Neuvonen PJ, and Backman JT (2007) Stereoselective interactionbetween the CYP2C8 inhibitor gemfibrozil and racemic ibuprofen. Eur J ClinPharmacol 63:463–469.

Tornio A, Niemi M, Neuvonen PJ, and Backman JT (2008b) Trimethoprim and theCYP2C8*3 allele have opposite effects on the pharmacokinetics of pioglitazone.Drug Metab Dispos 36:73–80.

Tornio A, Pasanen MK, Laitila J, Neuvonen PJ, and Backman JT (2005) Comparisonof 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (sta-tins) as inhibitors of cytochrome P450 2C8. Basic Clin Pharmacol Toxicol 97:104–108.

Totah RA and Rettie AE (2005) Cytochrome P450 2C8: substrates, inhibitors,pharmacogenetics, and clinical relevance. Clin Pharmacol Ther 77:341–352.

Tougou K, Gotou H, Ohno Y, and Nakamura A (2004) Stereoselective glucuronidation andhydroxylation of etodolac by UGT1A9 and CYP2C9 in man. Xenobiotica 34:449–461.

Tracy TS, Korzekwa KR, Gonzalez FJ, and Wainer IW (1999) Cytochrome P450isoforms involved in metabolism of the enantiomers of verapamil and norver-apamil. Br J Clin Pharmacol 47:545–552.

Tracy TS, Marra C, Wrighton SA, Gonzalez FJ, and Korzekwa KR (1997) In-volvement of multiple cytochrome P450 isoforms in naproxen O-demethylation.Eur J Clin Pharmacol 52:293–298.

Treluyer JM, Gueret G, Cheron G, Sonnier M, and Cresteil T (1997) Developmentalexpression of CYP2C and CYP2C-dependent activities in the human liver: in-vivo/in-vitro correlation and inducibility. Pharmacogenetics 7:441–452.

Tse S, Leung L, Raje S, Seymour M, Shishikura Y, and Obach RS (2014) Dispositionand metabolic profiling of [(14)C]cerlapirdine using accelerator mass spectrometry.Drug Metab Dispos 42:2023–2032.

Turpeinen M, Uusitalo J, Jalonen J, and Pelkonen O (2005) Multiple P450 substratesin a single run: rapid and comprehensive in vitro interaction assay. Eur J PharmSci 24:123–132.

Turpeinen M, Uusitalo J, Lehtinen T, Kailajärvi M, Pelkonen O, Vuorinen J, Tapa-nainen P, Stjernschantz C, Lammintausta R, and Scheinin M (2013) Effects ofospemifene on drug metabolism mediated by cytochrome P450 enzymes in humansin vitro and in vivo. Int J Mol Sci 14:14064–14075.

Tzimas G and Nau H (2001) The role of metabolism and toxicokinetics in retinoidteratogenesis. Curr Pharm Des 7:803–831.

Ufer M, Svensson JO, Krausz KW, Gelboin HV, Rane A, and Tybring G (2004)Identification of cytochromes P450 2C9 and 3A4 as the major catalysts of phen-procoumon hydroxylation in vitro. Eur J Clin Pharmacol 60:173–182.

Unger M and Frank A (2004) Simultaneous determination of the inhibitory potencyof herbal extracts on the activity of six major cytochrome P450 enzymes usingliquid chromatography/mass spectrometry and automated online extraction. RapidCommun Mass Spectrom 18:2273–2281.

Václavíková R, Horský S, Simek P, and Gut I (2003) Paclitaxel metabolism in rat andhuman liver microsomes is inhibited by phenolic antioxidants. Naunyn Schmie-debergs Arch Pharmacol 368:200–209.

Walle T, Walle UK, Kumar GN, and Bhalla KN (1995) Taxol metabolism and dis-position in cancer patients. Drug Metab Dispos 23:506–512.

Walles M, Wolf T, Jin Y, Ritzau M, Leuthold LA, Krauser J, Gschwind HP, CarcacheD, Kittelmann M, and Ocwieja M (2013) Metabolism and disposition of themetabotropic glutamate receptor 5 antagonist (mGluR5) mavoglurant (AFQ056) inhealthy subjects. Drug Metab Dispos 41:1626–1641.

Walsky RL, Gaman EA, and Obach RS (2005a) Examination of 209 drugs for in-hibition of cytochrome P450 2C8. J Clin Pharmacol 45:68–78.

Walsky RL and Obach RS (2004) Validated assays for human cytochrome P450 ac-tivities. Drug Metab Dispos 32:647–660.

Walsky RL, Obach RS, Gaman EA, Gleeson JP, and Proctor WR (2005b) Selective in-hibition of human cytochrome P4502C8 by montelukast.DrugMetab Dispos 33:413–418.

Walsky RL, Obach RS, Hyland R, Kang P, Zhou S, West M, Geoghegan KF, Helal CJ,Walker GS, and Goosen TC (2012) Selective mechanism-based inactivation ofCYP3A4 by CYP3cide (PF-04981517) and its utility as an in vitro tool for de-lineating the relative roles of CYP3A4 versus CYP3A5 in the metabolism of drugs.Drug Metab Dispos 40:1686–1697.

VandenBrink BM, Davis JA, Pearson JT, Foti RS, Wienkers LC, and Rock DA (2012)Cytochrome p450 architecture and cysteine nucleophile placement impactraloxifene-mediated mechanism-based inactivation. Mol Pharmacol 82:835–842.

VandenBrink BM, Foti RS, Rock DA, Wienkers LC, and Wahlstrom JL (2011)Evaluation of CYP2C8 inhibition in vitro: utility of montelukast as a selectiveCYP2C8 probe substrate. Drug Metab Dispos 39:1546–1554.

Wang B, Sanchez RI, Franklin RB, Evans DC, and Huskey SE (2004) The in-volvement of CYP3A4 and CYP2C9 in the metabolism of 17 alpha-ethinylestradiol.Drug Metab Dispos 32:1209–1212.

Wang JS and DeVane CL (2003) Involvement of CYP3A4, CYP2C8, and CYP2D6 inthe metabolism of (R)- and (S)-methadone in vitro. Drug Metab Dispos 31:742–747.

Wang JS, Neuvonen M, Wen X, Backman JT, and Neuvonen PJ (2002) Gemfibrozilinhibits CYP2C8-mediated cerivastatin metabolism in human liver microsomes.Drug Metab Dispos 30:1352–1356.

Wang MZ, Saulter JY, Usuki E, Cheung YL, Hall M, Bridges AS, Loewen G,Parkinson OT, Stephens CE, and Allen JL (2006) CYP4F enzymes are the majorenzymes in human liver microsomes that catalyze the O-demethylation of theantiparasitic prodrug DB289 [2,5-bis(4-amidinophenyl)furan-bis-O-methyl-amidoxime]. Drug Metab Dispos 34:1985–1994.

Wang Y, Wang M, Qi H, Pan P, Hou T, Li J, He G, and Zhang H (2014a) Pathway-dependent inhibition of paclitaxel hydroxylation by kinase inhibitors and assess-ment of drug-drug interaction potentials. Drug Metab Dispos 42:782–795.

Wang Z, Wang S, Huang M, Hu H, Yu L, and Zeng S (2014b) Characterizing the effectof cytochrome P450 (CYP) 2C8, CYP2C9, and CYP2D6 genetic polymorphisms onstereoselective N-demethylation of fluoxetine. Chirality 26:166–173.

Vargens DD, Petzl-Erler ML, and Suarez-Kurtz G (2012) Distribution of CYP2Cpolymorphisms in an Amerindian population of Brazil. Basic Clin PharmacolToxicol 110:396–400.

Varma MV, Lin J, Bi YA, Kimoto E, and Rodrigues AD (2015) QuantitativeRationalization of Gemfibrozil Drug Interactions: Consideration of Transporters-


Enzyme Interplay and the Role of Circulating Metabolite Gemfibrozil 1-O-b-Glucuronide.Drug Metab Dispos 43:1108–1118.

Varma MV, Lin J, Bi YA, Rotter CJ, Fahmi OA, Lam JL, El-Kattan AF, Goosen TC,and Lai Y (2013) Quantitative prediction of repaglinide-rifampicin complex druginteractions using dynamic and static mechanistic models: delineating differentialCYP3A4 induction and OATP1B1 inhibition potential of rifampicin. Drug MetabDispos 41:966–974.

Varma MV, Scialis RJ, Lin J, Bi YA, Rotter CJ, Goosen TC, and Yang X (2014)Mechanism-based pharmacokinetic modeling to evaluate transporter-enzyme interplayin drug interactions and pharmacogenetics of glyburide. AAPS J 16:736–748.

Watanabe K, Yamaori S, Funahashi T, Kimura T, and Yamamoto I (2007) Cyto-chrome P450 enzymes involved in the metabolism of tetrahydrocannabinols andcannabinol by human hepatic microsomes. Life Sci 80:1415–1419.

Wattanachai N, Polasek TM, Heath TM, Uchaipichat V, Tassaneeyakul W, Tassa-neeyakul W, and Miners JO (2011) In vitro-in vivo extrapolation of CYP2C8-catalyzed paclitaxel 6a-hydroxylation: effects of albumin on in vitro kineticparameters and assessment of interindividual variability in predicted clearance.Eur J Clin Pharmacol 67:815–824.

Waxman DJ, Lapenson DP, Aoyama T, Gelboin HV, Gonzalez FJ, and Korzekwa K(1991) Steroid hormone hydroxylase specificities of eleven cDNA-expressed humancytochrome P450s. Arch Biochem Biophys 290:160–166.

Weber C, Funk C, Frank K, MacDonald A, and Charoin J (2005) In vitro studies andcomputer simulation of interactions between R483, a novel thiazolidinedione, andcytochrome P450 substrates. Clin Pharmacol Ther 77:P74.

Wen X, Wang JS, Backman JT, Kivistö KT, and Neuvonen PJ (2001) Gemfibrozil is apotent inhibitor of human cytochrome P450 2C9. Drug Metab Dispos 29:1359–1361.

Wen X, Wang JS, Backman JT, Laitila J, and Neuvonen PJ (2002) Trimethoprim andsulfamethoxazole are selective inhibitors of CYP2C8 and CYP2C9, respectively.Drug Metab Dispos 30:631–635.

Venepally P, Chen D, and Kemper B (1992) Transcriptional regulatory elements forbasal expression of cytochrome P450IIC genes. J Biol Chem 267:17333–17338.

Venkatakrishnan K, Schmider J, Harmatz JS, Ehrenberg BL, von Moltke LL, GrafJA, Mertzanis P, Corbett KE, Rodriguez MC, and Shader RI (2001) Relative con-tribution of CYP3A to amitriptyline clearance in humans: in vitro and in vivostudies. J Clin Pharmacol 41:1043–1054.

Ventura V, Solà J, Celma C, Peraire C, and Obach R (2011) In vitro metabolism ofirosustat, a novel steroid sulfatase inhibitor: interspecies comparison, metaboliteidentification, and metabolic enzyme identification. Drug Metab Dispos 39:1235–1246.

Vermeir M, Hemeryck A, Cuyckens F, Francesch A, Bockx M, Van Houdt J, SteemansK, Mannens G, Avilés P, and De Coster R (2009) In vitro studies on the metabolismof trabectedin (YONDELIS) in monkey and man, including human CYP reactionphenotyping. Biochem Pharmacol 77:1642–1654.

Veronese ME, Doecke CJ, Mackenzie PI, McManus ME, Miners JO, Rees DL, GasserR, Meyer UA, and Birkett DJ (1993) Site-directed mutation studies of human livercytochrome P-450 isoenzymes in the CYP2C subfamily. Biochem J 289:533–538.

Whitfield LR, Porcari AR, Alvey C, Abel R, Bullen W, and Hartman D (2011) Effect ofgemfibrozil and fenofibrate on the pharmacokinetics of atorvastatin. J ClinPharmacol 51:378–388.

Whomsley E, Brochot A, Dell’Aiera S, Delepine X, and Espié P (2007) Identification ofthe cytochrome P450 isoforms responsible for the hydroxylation of Brivaracetam,in AAPS Annual Meeting and Exposition, San Diego, California (November 12-16,2007). AAPS J 9 (Suppl 2):T3408.

Vicente J, González-Andrade F, Soriano A, Fanlo A, Martínez-Jarreta B, and Sinués B(2014) Genetic polymorphisms of CYP2C8, CYP2C9 and CYP2C19 in EcuadorianMestizo and Spaniard populations: a comparative study.Mol Biol Rep 41:1267–1272.

Vickers AE, Sinclair JR, Zollinger M, Heitz F, Glänzel U, Johanson L, and Fischer V(1999) Multiple cytochrome P-450s involved in the metabolism of terbinafinesuggest a limited potential for drug-drug interactions. Drug Metab Dispos 27:1029–1038.

Vickers AE, Zollinger M, Dannecker R, Tynes R, Heitz F, and Fischer V (2001) Invitro metabolism of tegaserod in human liver and intestine: assessment of druginteractions. Drug Metab Dispos 29:1269–1276.

Vincent SH, Reed JR, Bergman AJ, Elmore CS, Zhu B, Xu S, Ebel D, Larson P, ZengW, and Chen L (2007) Metabolism and excretion of the dipeptidyl peptidase 4inhibitor [14C]sitagliptin in humans. Drug Metab Dispos 35:533–538.

Williams PA, Cosme J, Ward A, Angove HC, Matak Vinkovi�c D, and Jhoti H (2003)Crystal structure of human cytochrome P450 2C9 with bound warfarin. Nature424:464–468.

Winter HR and Unadkat JD (2005) Identification of cytochrome P450 and arylamineN-acetyltransferase isoforms involved in sulfadiazine metabolism. Drug MetabDispos 33:969–976.

Winter HR, Wang Y, and Unadkat JD (2000) CYP2C8/9 mediate dapsoneN-hydroxylation at clinical concentrations of dapsone. Drug Metab Dispos 28:865–868.

Wong H, Chen JZ, Chou B, Halladay JS, Kenny JR, La H, Marsters JC Jr, Plise E,Rudewicz PJ, and Robarge K (2009) Preclinical assessment of the absorption,distribution, metabolism and excretion of GDC-0449 (2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide), an orally bioavailable systemic Hedgehogsignalling pathway inhibitor. Xenobiotica 39:850–861.

Wu X, Zuo J, Guo T, and Yuan L (2013) CYP2C8 polymorphism frequencies amongHan, Uighur, Hui, and Mongolian Chinese populations. Genet Test Mol Biomarkers17:104–108.

Wu J, Shaw J, Dubaisi S, Valeriote F, and Li J (2014) In vitro metabolism and drug-drug interaction potential of UTL-5g, a novel chemo- and radioprotective agent.Drug Metab Dispos 42:2058–2067.

Xiaoping L, Zhong F, and Tan X (2013) Cytochrome P450 2C8 and drug metabolism.Curr Top Med Chem 13:2241–2253.

Xu C and Desta Z (2013) In vitro analysis and quantitative prediction of efavirenzinhibition of eight cytochrome P450 (CYP) enzymes: major effects on CYPs 2B6,2C8, 2C9 and 2C19. Drug Metab Pharmacokinet 28:362–371.

Yajima K, Uno Y, Murayama N, Uehara S, Shimizu M, Nakamura C, Iwasaki K,Utoh M, and Yamazaki H (2014) Evaluation of 23 lots of commercially availablecryopreserved hepatocytes for induction assays of human cytochromes P450. DrugMetab Dispos 42:867–871.

Yamamoto T, Suzuki A, and Kohno Y (2002) Application of microtiter plate assay toevaluate inhibitory effects of various compounds on nine cytochrome P450 isoformsand to estimate their inhibition patterns. Drug Metab Pharmacokinet 17:437–448.

Yamazaki H, Inoue K, Hashimoto M, and Shimada T (1999a) Roles of CYP2A6 andCYP2B6 in nicotine C-oxidation by human liver microsomes. Arch Toxicol 73:65–70.

Yamazaki H, Shibata A, Suzuki M, Nakajima M, Shimada N, Guengerich FP,and Yokoi T (1999b) Oxidation of troglitazone to a quinone-type metabolite cata-lyzed by cytochrome P-450 2C8 and P-450 3A4 in human liver microsomes. DrugMetab Dispos 27:1260–1266.

Yamazaki H and Shimada T (1999) Effects of arachidonic acid, prostaglandins, ret-inol, retinoic acid and cholecalciferol on xenobiotic oxidations catalysed by humancytochrome P450 enzymes. Xenobiotica 29:231–241.

Yamazaki H, Suzuki M, Tane K, Shimada N, Nakajima M, and Yokoi T (2000) Invitro inhibitory effects of troglitazone and its metabolites on drug oxidation ac-tivities of human cytochrome P450 enzymes: comparison with pioglitazone androsiglitazone. Xenobiotica 30:61–70.

Yamazaki M, Li B, Louie SW, Pudvah NT, Stocco R, Wong W, Abramovitz M,Demartis A, Laufer R, and Hochman JH (2005) Effects of fibrates on human or-ganic anion-transporting polypeptide 1B1-, multidrug resistance protein 2- and P-glycoprotein-mediated transport. Xenobiotica 35:737–753.

Yang J, He MM, Niu W, Wrighton SA, Li L, Liu Y, and Li C (2012) Metaboliccapabilities of cytochrome P450 enzymes in Chinese liver microsomes comparedwith those in Caucasian liver microsomes. Br J Clin Pharmacol 73:268–284.

Yang J, Liao M, Shou M, Jamei M, Yeo KR, Tucker GT, and Rostami-Hodjegan A(2008) Cytochrome p450 turnover: regulation of synthesis and degradation,methods for determining rates, and implications for the prediction of drug inter-actions. Curr Drug Metab 9:384–394.

Yang TJ, Shou M, Korzekwa KR, Gonzalez FJ, Gelboin HV, and Yang SK (1998) Roleof cDNA-expressed human cytochromes P450 in the metabolism of diazepam.Biochem Pharmacol 55:889–896.

Yano JK, Wester MR, Schoch GA, Griffin KJ, Stout CD, and Johnson EF (2004) Thestructure of human microsomal cytochrome P450 3A4 determined by X-ray crys-tallography to 2.05-A resolution. J Biol Chem 279:38091–38094.

Yasar U, Lundgren S, Eliasson E, Bennet A, Wiman B, de Faire U, and Rane A (2002)Linkage between the CYP2C8 and CYP2C9 genetic polymorphisms. BiochemBiophys Res Commun 299:25–28.

Ye L, Tang L, Gong Y, Lv C, Zheng Z, Jiang Z, and Liu Z (2011) Characterization ofmetabolites and human P450 isoforms involved in the microsomal metabolism ofmesaconitine. Xenobiotica 41:46–58.

Yeo CW, Lee SJ, Lee SS, Bae SK, Kim EY, Shon JH, Rhee BD, and Shin JG (2011)Discovery of a novel allelic variant of CYP2C8, CYP2C8*11, in Asian populations and itsclinical effect on the rosiglitazone disposition in vivo. Drug Metab Dispos 39:711–716.

Yi P, Hadden C, Kulanthaivel P, Calvert N, Annes W, Brown T, Barbuch RJ, ChaudharyA, Ayan-Oshodi MA, and Ring BJ (2010) Disposition andmetabolism of semagacestat, agamma-secretase inhibitor, in humans. Drug Metab Dispos 38:554–565.

Yoshida K, Maeda K, and Sugiyama Y (2012) Transporter-mediated drug–drug in-teractions involving OATP substrates: predictions based on in vitro inhibitionstudies. Clin Pharmacol Ther 91:1053–1064.

Yu L, Jiang Y, Wang L, Sheng R, Hu Y, and Zeng S (2013a) Metabolism of BYZX inhuman liver microsomes and cytosol: identification of the metabolites and meta-bolic pathways of BYZX. PLoS One 8:e59882.

Yu L, Shi D, Ma L, Zhou Q, and Zeng S (2013b) Influence of CYP2C8 polymorphismson the hydroxylation metabolism of paclitaxel, repaglinide and ibuprofen enan-tiomers in vitro. Biopharm Drug Dispos 34:278–287.

Yuan Y, Qiu X, Nikoli�c D, Chen SN, Huang K, Li G, Pauli GF, and van Breemen RB(2014) Inhibition of human cytochrome P450 enzymes by hops (Humulus lupulus)and hop prenylphenols. Eur J Pharm Sci 53:55–61.

Zeldin DC, DuBois RN, Falck JR, and Capdevila JH (1995) Molecular cloning, ex-pression and characterization of an endogenous human cytochrome P450 arachi-donic acid epoxygenase isoform. Arch Biochem Biophys 322:76–86.

Zelko I, Sueyoshi T, Kawamoto T, Moore R, and Negishi M (2001) The peptide nearthe C terminus regulates receptor CAR nuclear translocation induced by xen-ochemicals in mouse liver. Mol Cell Biol 21:2838–2846.

Zhang D, Wang L, Chandrasena G, Ma L, Zhu M, Zhang H, Davis CD,and Humphreys WG (2007a) Involvement of multiple cytochrome P450 and UDP-glucuronosyltransferase enzymes in the in vitro metabolism of muraglitazar. DrugMetab Dispos 35:139–149.

Zhang JW, Liu Y, Cheng J, Li W, Ma H, Liu HT, Sun J, Wang LM, He YQ, and WangY (2007b) Inhibition of human liver cytochrome P450 by star fruit juice. J PharmPharm Sci 10:496–503.

Zhang YY, Liu Y, Zhang JW, Ge GB, Liu HX, Wang LM, Sun J, and Yang L (2009a)C-7 configuration as one of determinants in taxanes metabolism by human cyto-chrome P450 enzymes. Xenobiotica 39:903–914.

Zhang YY, Liu Y, Zhang JW, Ge GB, Wang LM, Sun J, and Yang L (2009b) Char-acterization of human cytochrome P450 isoforms involved in the metabolism of7-epi-paclitaxel. Xenobiotica 39:283–292.

Zharikova OL, Fokina VM, Nanovskaya TN, Hill RA, Mattison DR, Hankins GD,and Ahmed MS (2009) Identification of the major human hepatic and placentalenzymes responsible for the biotransformation of glyburide. Biochem Pharmacol78:1483–1490.

Zheng YF, Bae SH, Choi EJ, Park JB, Kim SO, Jang MJ, Park GH, Shin WG, Oh E,and Bae SK (2014) Evaluation of the in vitro/in vivo drug interaction potential ofBST204, a purified dry extract of ginseng, and its four bioactive ginsenosides

240 Backman et al.

through cytochrome P450 inhibition/induction and UDP-glucuronosyltransferaseinhibition. Food Chem Toxicol 68:117–127.

Zheng YF, Bae SH, Kwon MJ, Park JB, Choi HD, Shin WG, and Bae SK (2013)Inhibitory effects of astaxanthin, b-cryptoxanthin, canthaxanthin, lutein, andzeaxanthin on cytochrome P450 enzyme activities. Food Chem Toxicol 59:78–85.

Zhong DN, Wu JZ, and Li GJ (2013) Association between CYP2C8 (rs1934951)polymorphism and bisphosphonate-related osteonecrosis of the jaws in patients onbisphosphonate therapy: a meta-analysis. Acta Haematol 129:90–95.

Zhou D, Andersson TB, and Grimm SW (2011) In vitro evaluation of potential drug-drug interactions with ticagrelor: cytochrome P450 reaction phenotyping, in-hibition, induction, and differential kinetics. Drug Metab Dispos 39:703–710.

Zhou L, Naraharisetti SB, Liu L, Wang H, Lin YS, Isoherranen N, Unadkat JD,Hebert MF, and Mao Q (2010) Contributions of human cytochrome P450 enzymesto glyburide metabolism. Biopharm Drug Dispos 31:228–242.

Zhu L, Liu X, Zhu L, Zhang X, Fu X, Huang J, and Yuan M (2014) Identification ofhuman cytochrome P450 isozymes involved in the metabolism of naftopidil enan-tiomers in vitro. J Pharm Pharmacol 66:1534–1551.

Zou L, Harkey MR, and Henderson GL (2002) Effects of herbal components on cDNA-expressed cytochrome P450 enzyme catalytic activity. Life Sci 71:1579–1589.

Zvyaga T, Chang SY, Chen C, Yang Z, Vuppugalla R, Hurley J, Thorndike D, WagnerA, Chimalakonda A, and Rodrigues AD (2012) Evaluation of six proton pump in-hibitors as inhibitors of various human cytochromes P450: focus on cytochromeP450 2C19. Drug Metab Dispos 40:1698–1711.


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