drug interactions with herbal medicines - natural know ho€¦ · 1. mechianisms of herbal...

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DCWICU/ ADTI/^IC ClinPhormacoWnet2012;51 (2): 77-104 •VCYICW i^KIIV^LC O312-5963/12/0CIO2-flO77/S49,95/0 ® 2012 Adb Data Intormctlon BV, All rights reserved. Drug Interactions with Herbal Medicines Shaojun Shi^ and Ulrich Klotz^'^ 1 Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China 2 Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany 3 University of Tuebingen, Tuebingen, Germany Contents Abstract 78 1, Mechanisms of Herbal Medicine-Drug Interactions 79 1.1 Inhibition of Cytochrome P450 (CYP) 79 .,2 Induction of CYP , 79 .,3 Inhibition or Induction of Drug Transporters 79 2, Evaluation of Herbal Medicine-Drug Interactions 80 2.1 Black Cohosh 80 2.1.1 In Vtfro and Animal Studies 80 2.1.2 Clinical Studies \ 80 2.2 Echinacea 80 2.2.1 In Vitro and Animal Studies 80 2.2.2 Clinical Studies 86 2.3 Garlic 86 2.3.1 In V/fro and Animal Studies 86 2.3.2 Clinical Studies 87 2.4 Ginkgo 87 2.4.1 In Vitro and Animal Studies 88 2.4.2 Clinical Studies _ 88 2.5 Goldenseal 89 2.5.1 In Vitro and Animal Studies 89 2.5.2 Clinical Studies 89 2.6 Kava 90 2.6.1 In Vitro and Animal Studies 90 2.6.2 Clinical Studies 90 2.7 Milk Thistle 90 2.7.1 In Vitro and Animal Studies 90 2.7.2 Clinical Studies ,' 91 2.8 Ponax ginseng , 92 2.8.1 In Vitroanó Animal Studies 92 2.8.2 Ciinical Studies 92 2.9 Ponax quinquefolius 92 2.9.1 Animal Studies , 93 2.9.2 Clinicai Studies 93 2.10 Saw Palmetto 93 2.10.1 In Vitroand Laboratory Studies 93 2.10.2 Ciinical Studies 93 2.11 St John's Wort 93

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Page 1: Drug Interactions with Herbal Medicines - Natural Know Ho€¦ · 1. Mechianisms of Herbal Medicine-Drug interoctions As with any drug interaction, herbal medicine-drug inter-actions

DCWICU/ A D T I / ^ I C ClinPhormacoWnet2012;51 (2): 77-104•VCYICW i^KIIV^LC O312-5963/12/0CIO2-flO77/S49,95/0

® 2012 Adb Data Intormctlon BV, All rights reserved.

Drug Interactions with Herbal MedicinesShaojun Shi^ and Ulrich Klotz^'^

1 Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China2 Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany3 University of Tuebingen, Tuebingen, Germany

Contents

Abstract 781, Mechanisms of Herbal Medicine-Drug Interactions 79

1.1 Inhibition of Cytochrome P450 (CYP) 79

.,2 Induction of CYP , 79

.,3 Inhibition or Induction of Drug Transporters 79

2, Evaluation of Herbal Medicine-Drug Interactions 80

2.1 Black Cohosh 80

2.1.1 In Vtfro and Animal Studies 80

2.1.2 Clinical Studies \ 80

2.2 Echinacea 80

2.2.1 In Vitro and Animal Studies 80

2.2.2 Clinical Studies 86

2.3 Garlic 86

2.3.1 In V/fro and Animal Studies 86

2.3.2 Clinical Studies 87

2.4 Ginkgo 87

2.4.1 In Vitro and Animal Studies 88

2.4.2 Clinical Studies _ 88

2.5 Goldenseal 89

2.5.1 In Vitro and Animal Studies 89

2.5.2 Clinical Studies 89

2.6 Kava 90

2.6.1 In Vitro and Animal Studies 90

2.6.2 Clinical Studies 90

2.7 Milk Thistle 90

2.7.1 In Vitro and Animal Studies 90

2.7.2 Clinical Studies ,' 91

2.8 Ponax ginseng , 92

2.8.1 In Vitroanó Animal Studies 92

2.8.2 Ciinical Studies 92

2.9 Ponax quinquefolius 92

2.9.1 Animal Studies , 93

2.9.2 Clinicai Studies 93

2.10 Saw Palmetto 93

2.10.1 In Vitroand Laboratory Studies 93

2.10.2 Ciinical Studies • 93

2.11 St John's Wort 93

Page 2: Drug Interactions with Herbal Medicines - Natural Know Ho€¦ · 1. Mechianisms of Herbal Medicine-Drug interoctions As with any drug interaction, herbal medicine-drug inter-actions

78 Shi & Klotz

2.11.1 In V/fro and Animal Studies 93

2.11.2 Ciinical Studies 943. Conciusions 95

AbStrQCt In recent years, the issue of herbal medicine-drug interactions has generated significant concern. Suchinteractions can increase the risk for an individual patient, especially with regard to drugs with a narrowtherapeutic index (e.g. warfarin, ciclosporin and digoxin). The present article summarizes herbal medicine-drug interactions involving mainly inhibition or induction of cytochrome P450 enzymes and/or drug trans-porters. An increasing number of in vitro and animal studies, case reports and clinical trials evaluating suchinteractions have been reported, and the majority of the interactions may be difficult to predict. Potentialpharmacodynamic and/or pharmacokinetic interactions of commonly used herbal medicines (black cohosh,garlic, Ginkgo, goldenseal, kava, milk thistle, Panax ginseng, Panax quinquefolius, saw palmetto and St John'swort) with conventional drugs are presented, and sometimes the results are contradictory. Clinical implicationsof herbal medicine-drug interactions depend on a variety of factors, such as the co-administered drugs, thepatient characteristics, the origin of the herbal medicines, the composition of their constituents and the applieddosage regimens. To optimize the use of herbal medicines, further controlled studies are urgently needed toexplore their potential for interactions with conventional drugs and to delineate the underlying mechanisms.

Herbal medicine - also called botanical medicine, medical her-balism, phytotherapy or phytomedicine - refers to use of variousparts of a plant (seeds, berries, roots, leaves, bark or flowers) formedicinal purposes. Herbal medicines have been widely usedfor a variety of conditions over thousands of years, and theyhave gained increasing popularity especially over the last dec-ade. Furthermore, they are often administered in combinationwith conventional drugs, raising the potential for pharmaco-kinetic and/or pharmacodynamic interactions.''"''1 There hasbeen increasing concern about their safety, potential toxicityand interactions with other drugs.f^"''*'

In general, herbal medicines are considered traditionalhealth aids, which are currently not subject to the same scrutinyand regulatory processes that apply to conventional and over-the-counter medicines. Manufacturers are exempted from pre-market safety and efficacy testing before releasing a herbalmedicine and from any post-marketing surveillance.f'^' Ad-ditionally, the use of herbal medicines is complicated by avariety of factors, including lack of scientific evidence of safetyand efficacy, lack of regulatory oversight, lack of quality con-trol and lack of knowledge about herbal medicine-drug inter-actions among patients and health care providers, as well asunder-reporting and underestimation of adverse effects. ' -' ^

Therefore, there is an urgent need to better understand themechanisms of potential herbal medicine-drug interactions andto provide more current information for clinical practice. Thepresent review provides evidence of potential pharmacokinetic

and/or pharmacodynamic interactions involving 11 commonherbal medicines, which are all widely used in the Western

The databases MEDLINE, Embase and the Cochrane Librarywere searched from their inception to June 2011, using the followingterms: 'herbal medicine', 'botanical medicine' and 'phytotherapy',in combination with 'drug interactions', 'adverse drug reaction','safety', 'toxicity', 'pharmacokinetics' and 'pharmacodynamics'.The names and primary active constituents of the 11 common herbalmedicines were .also used as keywords. No language restrictionswere imposed. Review articles were retrieved and searched toidentify additional relevant primary research articles. Clinicalstudies in human were all included and emphasized.

In vitro screening techniques and animal models play a majorrole in identifying possible herbal medicine-drug interactionsand thus could be used to initiate clinical studies. Therefore,data from in vitro and animal studies were also included toexplore the mechanisms of herbal drug interactions, which weregenerally excluded from several previous reviews. One shouldbe aware that extract constituents from herbal medicines mighthave some confounding effects. Some extract constituents avail-able in the in vitro tests are neither bioavailable nor relevantto the in vivo situation. For example, tannins can denature pro-teins and produce irrelevant in vitro results. Many ñavonoids areonly present in vivo in the form of their conjugates, whereas theyare present in the plant extracts in the form of their genuineglycosides.

© 2012 Adis Data Information BV. Aii rights reserved. Ciin Pharmacokinet 2012; 51 (2)

Page 3: Drug Interactions with Herbal Medicines - Natural Know Ho€¦ · 1. Mechianisms of Herbal Medicine-Drug interoctions As with any drug interaction, herbal medicine-drug inter-actions

Drug Interactions with Herbal Medicines 79

Furthermore, polymorphisms of genotypes, specificallythose found in certain ethnic groups, may influence herbalmedicine-drug interactions mediated through metabolic andtransport pathways. Therefore, the effects of pharmacogeneticson the safety and risks of herbal medicines and co-administereddrugs are also reviewed and discussed.

1. Mechianisms of Herbal Medicine-Drug interoctions

As with any drug interaction, herbal medicine-drug inter-actions can be explained by pharmacokinetic and pharmaco-dynamic mechanisms. Pharmacodynamic interactions occurwhen the pharmacological action of a herbal medicine sy-nergizes, augments or antagonizes the biological activity of aconventional drug.'''^ Although most herbal medicine-drug in-teractions are likely to be negative in nature, it is important torealize that a few interactions may have a beneficial effect byincreasing drug efficacy or diminishing potential side effects.For example, combined therapy with garlic (250mg/kg) andcaptopril demonstrated greater synergistic interaction with re-spect to the fall in blood pressure and angiotensin-convertingenzyme inhibition.t'^1 Silymarin (140 mg three times daily) incombination with desferrioxamine can be safely and effectivelyused in the treatment of iron-loaded patients as it has beenshown to have beneficial effects in thalassaemia patients.'"'The vast majority of potential herbal medicine-drug interac-tions are of pharmacokinetic origin, resulting in changes inabsorption (e.g. modulation of efflux and uptake transporters,complex formation, gastrointestinal motility and pH) and bio-transformation (e.g. inhibition or induction of drug-metabolizingenzymes) of the affected drug. Pharmacokinetic interactionsbecome clinically significant when considerable changes occurin pharmacokinetic parameters (e.g. the area under the plasmaconcentration-time curve [AUC], the maximum plasma con-centration [Cmax] or the elimination half-life [t ./J) of prescrip-tion medications, especially those with a narrow therapeuticindex, such as warfarin and digoxin.''"^1

The following sections will focus on pharmacokinetic inter-actions involving inhibition or induction of cytochrome P450(CYP) and/or drug transporters.['"^•^°1

1.1 Inhibition of Cytochrome P450 (CYP)

Inhibition of drug-metabolizing enzymes can be simply clas-sified into reversible and irreversible inhibition, on the basis of theunderlying mechanism.P'l Reversible inhibition is most commonand can be further divided into competitive, noncompetitive anduncompetitive inhibition. The most frequent type is simple com-

petition for the reactive site of the enzyme.P^l Herbal medicinessometimes inhibit CYP enzymes in a competitive/noncompetitivemixed manner, depending on the CYP species and the herbalconstituents.'^-'-^''] Irreversible inhibitors usually covalently mod-ify an enzyme, and therefore inhibition cannot be reversed.However, not all irreversible inhibitors form covalent adductswith their enzyme targets. Some reversible inhibitors bind sotightly to their target enzymes that they are essentially irrever-sible. Compared with reversible inhibition, mechanism-based(suicide) inhibition or irreversible inhibition of CYP isoforms,particularly CYP3A4, by herbal medicine is characterized bytime-, concentration- and NADPH-dependent blockade.P-^^-^^lThis type of inhibition can completely inactivate the metabo-lism of other drugs and may persist even after withdrawal ofherbal medicines.P^'-^*'

1.2 induction of CYP

Induction of CYP is characterized by promotion of geneactivation or messenger RNA (mRNA) synthesis or inhibitionof degradation of protein or mRNA.'^^' Induction is a slowregulatory process in contrast to the immediate response of CYPinhibition.'-'") The most prominent mechanisms for CYP induc-tion are ligand-dependent transcription activation of nuclearreceptors, such as pregnane X receptors (PXR), constitutiveandrostane receptors (CAR) or aryl hydrocarbon receptors(AhR).'3'-34] Species differences in CAR and PXR activationmake the clinical prediction of CYP induction difficult.' ''' ^^Herb-mediated inductive effects on CYP isoforms have been ofconcern for CYP3A, CYP2B6 and CYPl A2, and may result insubtherapeutic plasma concentrations leading to reduced effi-cacy of the drug, or even treatment failure.

1.3 inhibition or induction of Drug Transporters

In recent years, many drug transporters have been identifiedin humans. The best characterized transporter is P-glycoprotein(P-gp), the product of the MDRl gene (now known as ABCBl),which functions as a drug efflux pump. P-gp is located on theapical membrane of cells in the gastrointestinal tract, liver,kidney, lung, blood-brain barrier and placenta.'^*! Within in-testinal enterocytes, the role of P-gp is to actively secrete someabsorbed drugs back into the intestinal lumen. Therefore, in-hibition or induction of P-gp by herbal medicine can result inelevated or reduced drug concentrations, respectively. Like-wise, induction of P-gp appears to be regulated by the nuclearreceptors PXR or ' l

© 2012 Adis Data information BV. All rights reserved. Ciin Pharmacokinet 2012; 51 (2)

Page 4: Drug Interactions with Herbal Medicines - Natural Know Ho€¦ · 1. Mechianisms of Herbal Medicine-Drug interoctions As with any drug interaction, herbal medicine-drug inter-actions

80 Shi & Klotz

It has been observed that many drugs and herbal activeconstituents are co-substrates for both P-gp and CYP3A4. Inaddition, P-gp and CYP3A4 constitute a highly efficient barrierfor the bioavailability of many orally absorbed drugs.t^'"'''^ Theinterdependence of both drug metabolism and transport on thedisposition of drugs has gained considerable attention and istermed 'transport-metabolism interplay'.i'*^'''^^ Therefore, it issometimes difficult to evaluate the specific role played by eachof these two different mechanisms in changing the bioavail-ability and disposition of co-administered drugs.

2. Evaluation of Herbal Medicine-Drug Interactions

Potential herbal medicine-drug interactions have been reportedin a wide variety of laboratory, animal and human studies. Fur-thermore, herbal medicines have been shown to interact clinicallywith many conventional drugs (see table I). In the following sec-tions, we will provide some examples of how herbal medicinesaffect the pharmacokinetic and/or pharmacodynamic profiles ofconventional medications.

2.1 Black Cohosh

Black cohosh (Actaea racemosa) is one of the most frequentlyused herbal medications for menopausal vasomotor symp-toms.t'^'i Recently, a 'potential association' between black cohoshand hepatotoxicity has been suspected in Australia, Canada andEurope. However, one critical analysis demonstrated no causalrelationship between black cohosh treatment and the observedliver disease.''^^1 Likewise, a recent meta-analysis of five ran-domized controlled clinical trials involving a total of 1117women and a critical review suggested that black cohosh had noadverse effects on liver function.['''^•''''*i Furthermore, theDietary Supplement Information Expert Committee of the USPharmacopeia's Council of Experts outlined that pharmaco-kinetic and toxicological data did not reveal unfavourableinformation about black cohosh. Nevertheless the committeerecommended that black cohosh products should be labelledwith a statement of caution.''^^^ As black cohosh can inducehypotension, potential pharmacodynamic interactions may occurwhen it is taken with anaesthetics, antihypertensives or sedatives.

2.7.7 in Vitro and Animal Studies

Some preclinical studies have investigated the influence ofblack cohosh or its extract constituents on CYP.'^^''^^^ Micetreated with black cohosh 500mg/kg for 28 days showed that he-patic CYP3A11 was induced 7-fold, but no difference was found inthe small intestine and kidney, suggesting that upregulation ofCYP3A11 by black cohosh was liver specific. Interestingly,

mouse PXR was involved in the induction of CYP3A11, but thehuman counterpart was not.t^^' In addition, black cohosh ex-tracts (75% and 80% ethanol) can inhibit several CYP iso-enzymes (1A2, 2D6, 2C9, 3A4) in vitro and thus may have thepotential to induce herb-drug interactions.''"'^]

2.1.2 dinicai Studies

Four studies evaluated the potential interactions of black co-hosh with the probes midazolam (CYP3A4/5 substrate), caffeine(CYP1A2), chlorzoxazone (CYP2E1), debrisoquine (CYP2D6)and digoxin (P-gp).''' ""'''! In 12 healthy volunteers treated withblack cohosh 2180 mg/day for 28 days (a dose substantially higherthan the usual daily dose), weak (approximately 8%) inhibition ofCYP2D6 appeared to be of no clinical relevance.'*^! Likewise, noeffects on CYP3A4/5, CYP1A2 or CYP2A1 were found.''*^-'*'!Similarly, in 16 healthy volunteers receiving black cohosh80 mg/day for 14 days, CYP2D6 activity was not affected.'"^! Fi-nally, in 16 healthy volunteers receiving black cohosh 40 mg/dayfor 14 days, no significant effects on digoxin pharmacokineticswere observed, suggesting no influence on P-gp function.'''^

The results have shown that co-administration of blackcohosh hardly affects CYPs or P-gp. However, further studiesin humans are needed to demonstrate the safety of concomitantuse of black cohosh and conventional drugs.

2.2 Echinacea

Echinacea is an unspeciflc immunostimulant mainly used totreat and prevent infections of the upper respiratory tract, suchas the common cold and influenza.''^^^ Echinacea purpurea (L)Moench, Echinacea angustifolia (DC) Hell and Echinacea pal-lida (Nutt) Nutt represent the three main species. They possessphytochemical similarities, of which alkylamides are thoughtto be the chemical moieties responsible for any modulation ofCYP

2.2.1 in Vitro and Animal Studies

Conflicting results have been reported regarding the impact ofEchinacea on CYP activity. Echinacea extracts and alkylamidescan inhibit CYP3A4 activity with considerable variation in po-tency, depending on the model substrate that is used.''^""'^''!Weak inhibition of CYP3A4 activity with the probe 7-benzyl-oxy-4-trifluoromethylcoumarin was observed, but in the pre-sence of the model substrate resorufin benzyl ether, mildinduction was seen. A minor effect on CYP2D6 and moderateinhibition of CYP2C9 was noted with E. purpurea.^^^'*^

In cultured primary human hepatocytes, E. purpurea(4.74^73.5 (ig/mL) was able to inhibit CYP1A2, CYP2D6

© 2012 Adis Data information BV, Ali rights reserved. Ciin Piiarmacoi<inet2012; 51 (2)

Page 5: Drug Interactions with Herbal Medicines - Natural Know Ho€¦ · 1. Mechianisms of Herbal Medicine-Drug interoctions As with any drug interaction, herbal medicine-drug inter-actions

Drug Interactions with Herbal Medicines 81

Table I. Summary of clinical herbal medicine-drug interactions

Herbal medicine Conventional drug Clinical outcomes of interaction Possible mechanism References

Black cohosh

Echinacea

Garlic

Caffeine

Chiorzoxazone

Debrisoquine

Digoxin

Midazoiam

Caffeine

Chiorzoxazone

Darunavir

Debrisoquine

Dextromethorphan

Digoxin

Fexofenadine

Midazoiam

Lopinavir

Ritonavir

Tolbutamide

Warfarin

Alprazolam

Caffeine

Chiorzoxazone

Ciclosporin

Debrisoquine

Dextromethorphan

Docetaxel

Fluindione

Midazoiam

Paracetamol

(acetaminophen)

Pravastatin

Ritonavir

Saquinavir

Simvastatin

Warfarin

No effect on caffeine pharmacokinetics

No effect on chiorzoxazone pharmacokinetics

Mixed results. Increased debrisoquine urinary

recovery ratios by 7%; no effect in another trial

No effect on digoxin pharmacokinetics

No effect on midazoiam pharmacokinetics

Mixed results. Reduced oral clearance of caffeine;no effect in another trial

No effect on chiorzoxazone pharmacokinetics

No effect on darunavir pharmacokinetics

No effect on debrisoquine pharmacokinetics

No effect on dextromethorphan pharmacokinetics

No effect on digoxin pharmacokinetics

No effect on fexofenadine pharmacokinetics

Mixed results. Increased systemic clearance and

oral bioavailability of midazoiam; no effect In one trial;

decreased midazoiam AUC and increased oral

clearance of mldazolam in another trial

No effect on lopinavir pharmacokinetics

No effect on ritonavir pharmacokinetics

No effect on tolbutamide pharmacokinetics

Slightly increased clearance of S-warfarin; no

effect on warfarin pharmacodynamics

No effect on alprazolam pharmacokinetics

No effect on caffeine pharmacokinetics

Decreased 6-hydroxychlorzoxazone/chlorzoxazoneserum ratios

No effect on ciclosporin pharmacokinetics

No effect on debrisoquine pharmacokinetics

No effect on dextromethorphan pharmacokinetics

No significant effect on docetaxel pharmacokinetics

Decreased INR

No effect on midazoiam pharmacokinetics

No effect on paracetamol pharmacokinetics

No effect on pravastatin pharmacokinetics

No effect on ritonavir pharmacokinetics

Decreased saquinavir AUC and C^ax

No effect on simvastatin pharmacokinetics

One case report of increased INR; no effect onwarfarin pharmacokinetics or pharmacodynamics

None

None

Weak inhibition

of CYP2D6

None

None

44

44

44,45

46

44.47

Inhibition of CyP1A2 48,49

None

None

None

None

None

None

Induction of hepatic

CYP3A and inhibition

of intestinal CYP3A

None

None

None

Weak induction of

CYP2C9

None

None

Inhibition of CYP2E1

None

None

None

None

Unknown

None

None

None

Unknown

Induction of P-gp

None

None

48

50

45,48

49

51

52

48,49,52

52

50,52

49

53

54

55,56

55-57

58

55,56

54

59

60

55,56

61

62

63

62,64

62

65-67

Cor)tinued next page

® 2012 Adis Data Ihformattoh BV. Aii rights reserved. Ciin Pharmacai<inet 2012; 51 (2)

Page 6: Drug Interactions with Herbal Medicines - Natural Know Ho€¦ · 1. Mechianisms of Herbal Medicine-Drug interoctions As with any drug interaction, herbal medicine-drug inter-actions

82 Shi & Klotz

Tabie I. Contd

Herbal medicine Conventional drug Clinical outcomes of interaction Possible mechanism References

Ginkgo biloba Alprazolam

Bupropion

Caffeine

Chlorzoxazone

Cilostazol

Clopidogrel

Debrisoquine

Dextromethorphan

Diazepam

Diclofenac

Digoxin

Donepezil

Fexofenadine

Flurbiprofen

Lopinavir

Metformin

Midazolam

Nifedipine

Omeprazole

Ritonavir

Talinolol

Ticlopidine

Tolbutamide

Voriconazole

Warfarin

Goldenseal Caffeine

Chlorzoxazone

Ciolosporin

Debrisoquine

Digoxin

Indinavir

Midazolam

Decreased alprazolam AUC

No effect on bupropion pharmacokinetics

No effect on caffeine pharmacokinetics

No effect on chlorzoxazone pharmacokinetics

No enhancement of antiplatelet activity; can

potentiate the bleeding time prolongation

effect of cilostazol

No enhancement of antiplatelet activity

No effect on debrisoquine pharmacokinetics

No effect on dextromethorphan pharmacokinetics

No effect on diazepam pharmaookinetics

No effect on diclofenao pharmacokinetics

No significant effect on digoxin pharmacokinetics

No effect on donepezil pharmacokinetics

Mixed results. Increased plasma concentrations of

fexofenadine; no effect in another trial

No effect on flurbiprofen pharmacokinetics

No effect on lopinavir pharmacokinetics

No effect on metformin pharmacokinetics

Mixed results. No effect on midazolam

pharmacokinetics; increased midazolam AUC in

one trial; decreased midazolam AUC and Cmax i"

another trial

No effect on nifedipine pharmacokinetics

Decreased plasma concentrations of omeprazole

and omeprazole sulfone

No effect on ritonavir pharmacokinetics

Increased talinolol Cmax and AUC

No significant effect on ticlopidine pharmacokinetics

Mixed results. Decreased tolbutamide AUC;

no effect in another trial

No significant effect on voriconazole pharmacokinetics

No significant effect on warfarin pharmacokinetics orpharmacodynamics

No effect on caffeine pharmacokinetics

No effect on chlorzoxazone pharmaookinetics

Increased blood concentration of ciclosporin

Decreased 8-hour debrisoquine urinary recovery ratios

No significant effect on digoxin pharmacokinetics

No significant effect on indinavir pharmacokinetics

Increased midazolam AUC and C^ax

Weak inhibitionof CYP3A4

None

None

None

Unknown

None

None

None

None

None

None

None

Probable inhibition

of P-gp

None

None

None

Unknown

68

69

55,56

55,56

70

70

55,56

68

71

72

73

74

75,76

77

75

78

55,56,75,79

None

Induction of CYP2C19

None

Inhibition of P-gp

None

Possible effect on CYP2C9

None

None

None

None

Inhibition of CYP3A4

Inhibition of CYP2D6

None

None

Inhibition of CYP3A4/5

80

81

75

82,83

84-86

72,79

87

88

44

44

89,90

44,45

91

92

44,93

Continued next page

© 2012 Adis Data Intormation BV, Ail rights reserved. Ciin Pharmaooi<inet 2012; 51 (2)

Page 7: Drug Interactions with Herbal Medicines - Natural Know Ho€¦ · 1. Mechianisms of Herbal Medicine-Drug interoctions As with any drug interaction, herbal medicine-drug inter-actions

Drug Interactions with Herbal Medicines 83

Table I. Contd

Herbal medicine Conventional drug Clinical outcomes of interaction Possible mechanism ReferencesKava

Milk thistle

Alprazolam

Caffeine

Chlorzoxazone

Debrisoquine

Digoxin

Levodopa

Midazolam

Caffeine

Chlorzoxazone

Debrisoquine

Desferrioxamine

Digoxin

Indinavir

Irinotecan

Losartan

Metronidazole

Midazolam

Nifedipine

Ranitidine

Rosuvastatin

Talinolol

Ranax ginseng

Panax

quinquefoHus

Caffeine

Chlorzoxazone

Debrisoquine

Midazolam

Nifedipine

Warfarin

Indinavir

Warfarin

Zidovudine

Coma (lethargy, disorientation)

No effect on caffeine pharmacokinetics

Decreased 6-hydroxychlorzoxazone/chlorzoxazoneserum ratios

No effect on debrisoquine pharmacokinetics

No significant effect on digoxin pharmacokinetics

Reduced efficacy

No effect on midazolam pharmacokinetics

No effect on caffeine pharmacokinetics

No effect on chlorzoxazone pharmacokinetics

No effect on debrisoquine pharmacokinetics

Beneficial effects

No significant effect on digoxin pharmacokinetics

No significant effect on indinavir pharmacokinetics

No significant effect on irinotecan pharmacokinetics

Increased losartan AUC; decreased metabolicratio of losartan

Increased clearance of metronidazole;

decreased t,, , C^ax and AUC

No effect on midazolam pharmacokinetics

No significant effect on nifedipine pharmacokinetics

No effect on ranitidine pharmacokinetics

No significant effect on rosuvastatinpharmacokinetics

Increased talinolol C^ax and AUC;decreased talinolol oral clearance

No effect on caffeine pharmacokinetics

No effect on chlorzoxazone pharmacokinetics

Weak or no effect on debrisoquine

pharmacokinetics

No effect on midazolam pharmacokinetics

Increased plasma concentration of nifedipine

No effect on warfarin pharmacokineticsor pharmacodynahiics

No effect on indinavir pharmacokinetics

Reduced anticoagulant effect of warfarin

No effect on zidovudine pharmacokinetics

Additive effect onGABA receptor

None

Inhibition of CYP2E1

None

None

None

None

None

None

None

Unknown

None

None

None

inhibition of CYP2C9

Induction of both intestinalP-gp and CYP3A4

None

None

None

None

Inhibition of P-gp

None

None

Weak or no effect

on CYP2D6

None

Unknown

None

94

44

44

44,45

91

94

44,93

48

48

45,48

19

46

95-97

98

99

100

47,48

101

102

103

104

55,56

55,56

55,56

55,56

105

106-108

None

None

None

109

110

111

Continued next page

© 2012 Adis Data information BV, Aii rights reserved. Ciin Pharmacoi<inet2012:51 (2)

Page 8: Drug Interactions with Herbal Medicines - Natural Know Ho€¦ · 1. Mechianisms of Herbal Medicine-Drug interoctions As with any drug interaction, herbal medicine-drug inter-actions

84 Shi & Klotz

Table I. Contd

Herbal medicine Conventional drug Clinical outcomes of interaction Possible mechanism References

Saw palmetto Alprazolam

Caffeine

Chlorzoxazone

Debrisoquine

Dextromethorphan

Midazolam

No effect on alprazolam pharmaookinetics None

No effect on caffeine pharmacokinetics None

No effect on chlorzoxazone pharmacokinetios None

No effect on debrisoquine pharmacokinetics None

No effect on dextromethorphan pharmacokinetics None

No effect on midazolam pharmacokinetics None

112

48

48

48

112

48

St John's wort Alprazolam

Amitriptyline

Atorvastatin

Bupropion

Buspirone

Caffeine

Carbamazepine

Chlorzoxazone

Cimetidine

Ciclosporin

Debrisoquine

Dextromethorphan

Digoxin

Erythromycin

Fexofenadine

Finasteride

Fluoxetine

Gliclazide

Ibuprofen

Imatinib

Indinavir

Irinotecan

Ivabradine

Mixed results. Decreased alprazolam AUC and l^;

weak or no effect in two trials

Decreased amitriptyline AUC

Reduced efficacy of atorvastatin

Decreased bupropion AUC

Serotonin syndrome

Mixed results. No effect on caffeine pharmacokinetics;

increased metabolic ratios only in females in one trial

Mixed results. Decreased pseudohypericin AUC;

no effect on carbamazepine pharmacokinetics in

another trial

Increased 6-hydroxychlorzoxazone/chlorzoxazone

serum ratios

Increased hypericin AUC

Decreased ciclosporin AUC and C^ax

No effect on debrisoquine pharmacokinetics

No effect on dextromethorphan pharmacokinetios

Mixed results. Decreased digoxin AUC and C^axl noeffect in one trial using a low-dose hyperforin extract

Increased erythromycin metabolism

Mixed results. Decreased fexofenadine plasma

concentration; increased fexofenadine C^ax after

single dose

Decreased finasteride AUC, C^ax and ty

Serotonin syndrome

Decreased gliclazide AUC and ti^;

increased apparent clearance

No effect on ibuprofen pharmacokinetics

Decreased imatinib AUC, C^ax and ti^

Decreased indinavir AUC

Decreased plasma concentrations of the activemetabolite SN-38

Decreased ivabradine AUC and C^ax

Induction of CYP3A4 113-115

Induction of CYP3A4 or P-gp 116

I nduction of CYP3A4 and P-gp 117

Induction of CYP2B6 118

Additive effect on serotonin 119

reuptake

None 55,56,113,120-122

Induction of CYP3A4

Induction of CYP2E1

123,124

55,56

Inhibition of CYP3A4

Induction of CYP3A4 and/or

P-gp

None

None

Induction of P-gp

Induction of CYP3A4

Induction of P-gp

Induction of CYP3A4

Additive effect on serotonin

reuptake

Unknown

None

Induction of CYP3A4

Induction of CYP3A4

Induction of CYP3A4

Induction of CYP3A4

124

125-128

45,55,56,129

114,115,120,121

51,113,130-132

130

125,133,134

135

136

137

138

139-141

142

143

144

Continued next page

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Drug Interactions with Herbal Medicines 85

Table I. Contd

Herbal medicine Conventional drug Clinical outcomes of interaction Possible mechanism ReferencesMephenytoin

Methadone

Midazolam

Mycophenolic acid

Nevirapine

Nifedipine

Omeprazole

Oral contraceptive

Pravastatin

Prednisone

Ouazepam

Ritonavir

Simvastatin

Talinolol

Tacrolimus

Theophylline

Tolbutamide

Verapamil

Voriconazole

Warfarin

Zolpidem

Increased urinary 4'-hydroxymephenytoinexcretion

Decreased methadone blood concentrations;

induced withdrawal symptoms

Mixed results. Decreased midazolam AUC;

weak effect in two trials with low hyperforin content;

no effect with short-term administration in one trial

No effect on mycophenolic acid pharmacokinetics

Decreased nevirapine plasma concentration

Decreased nifedipine AUC

Decreased omeprazole AUC and C^ax

Mixed results. Increased metabolism of oral

contraceptive and reduced efficacy; no effect in

one trial using a low-dose hyperforin extract

No effect on pravastatin pharmacokinetics

No significant effect on prednisone pharmacokinetics

Decreased quazepam AUC and C^ax

Increased midazolam AUC when co-administered

with St John's wort and ritonavir

Decreased plasma concentration of simvastatin

Decreased talinolol AUC

Decreased tacrolimus AUC; increased apparentoral clearance

Mixed results. No significant effect on theophylline

pharmacokinetics; decreased theophylline

plasma concentration in one case report

No effect on tolbutamide pharmacokinetics

Decreased verapamil AUC and C^ax

Increased voriconazole AUC 10 hours after

administration; decreased voriconazole AUC

on day 15

Increased apparent clearance of warfarin;decreased INR

Decreased zolpidem AUC and C^ax

Induction of CYP2C19 122

Induction of CYP3A4 or P-gp 145

Induction of CYP3A4 (primarily

intestinal)

None

Induction of CYP3A4

Induction of CYP3A4

Induction of CYP3A4 and

CYP2C19

Induction of CYP3A4

None

None

Induction of CYP3A4

55,56,121,125,134146-148

149

150,151

152

153

154-158

159

160

161

Predominant CYP3A4 inhibition 162

Induction of CYP3A4 159

Induction of intestinal P-gp 163

Induction of CYP3A4 and P-gp 149,164

None 165,166

None 113,121

Induction of intestinal CYP3A4 167

Modulation of CYP2C19 168,169

Induction of CYP3A4

Induction of CYP3A4

106

170AUC=area under the plasma concentration-time curve; C^ax = maximum plasma concentration; CYPINR = international normalized ratio; P-gp = P-glycoprotein; ti^=elimination half-life,

= cytochrome P450; GABA=gamma-aminobutyric acid;

and CYP3A4, but CYP2C19 and CYP2E1 were not affected.Importantly, the inhibitory potency was dependent on the al-kylamide content.t'^^"'^^! However, E. purpurea alkylamidesshowed significant inhibition of CYP2E1 at concentrations aslow as 25 nmol/L,['^^] Ethanolic extracts oiEchinacea containing3.7% polyphenolic compounds can also both inhibit the ex-pression of CYP3A1/2 and induce CYPlAl and

In addition, E. purpurea can inhibit P-gp activity.''^^' In intestinalCaco-2 cells, E. purpurea (from 0.4 to 6,36 mg dry weight/mL) dimin-ished P-gp activity in a dose-dependent manner,''^'' In the hu-man proximal tubule HK-2 cell line, N-hexane root extracts fromE. pallida, E. angustifolia and E. purpurea were able to reduce P-gpactivity, and E. pallida was the most active species.'' ^^ In humanembryonic kidney 293 cells, 270 ng/mL of an E. purpurea extract

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86 Shi & Klotz

inhibited the infltix of another transporter protein, organic anion-transporting polypeptide (OATP)-B, by 55.5%.'"^' Overall, E. pur-purea is likely to inhibit drug transport by P-gp and other transporters.

2.2.2 Clinical Studies

In 12 healthy subjects receiving 1600 mg/day of E. purpurea rootfor 8 days, CYP activities were assessed using caffeine (CYP1A2),tolbutamide (CYP2C9), dextromethorphan (CYP2D6) and mid-azoiam (hepatic and intestinal CYP3A). E. purpurea root sig-nificantly reduced oral clearance of caffeine (27%) but not thatof tolbutamide and dextromethorphan. The activity of CYP3Aat hepatic and intestinal sites was selectively modulated, assystemic clearance of midazoiam following intravenous ad-ministration was significantly reduced by 34% (p = 0.003), butoral clearance (following oral administration) was not altered.Furthermore, hepatic and intestinal availability were signi-ficantly affected in opposite directions. Whether the interactionwill lead to inhibition or induction depends on the hepatic andintestinal extraction ratios of the particular CYP3A sub-strate.''*'^ Two other clinical trials suggested that E. purpurea(801 mg/day or 1600 mg/day) had no significant effect on theactivities of CYP1A2, CYP2D6, CYP2E1 and CYP3A4.'45.48]Furthermore, Echinacea (267 mg three times daily) did not af-fect the disposition of digoxin; therefore, P-gp-mediated druginteractions are unlikely to occur with Echinacea.^^^^

In 15 HIV-infected patients, E. purpurea treatment (500 mgevery 6 hours) for 14 days did not change the overall pharma-cokinetics of darunavir or ritonavir.'^"' Likewise, in 13 healthyvolunteers, the pharmacokinetics of lopinavir or ritonavir werenot significantly altered by co-administration of E. purpurea(500 mg three times daily) for 14 days.'^^' In contrast, after 28days oí E. purpurea co-administration (500 mg three times daily),the AUC of midazoiam was significantly decreased (p = 0.008)and, consequently, oral clearance was increased (p = 0.02),whereas no effect on the pharmacokinetics of fexofenadine wasfound, indicating induction of CYP3A but no effect on P-gp.'^^)

Additionally, in 12 healthy subjects, concomitant treatmentwith Echinacea (1275mg four times daily containing 600 mgof £•. angustifolia root and 675 mg oí E. purpurea root) shghtlyincreased oral clearance of S-warfarin but did not have aclinically significant effect on warfarin pharmacodynamics.'^^^

Although the potential for Echinacea to inhibit CYPs or P-gpneeds further investigation, the currently available evidence in-dicates that Echinacea does not appear to pose a risk to consumers.

2.3 Garlic

Garlic (Allium sativum) has been generally used for thetreatment of hypercholesterolaemia, prevention of arterio-

sclerosis, and a variety of other conditions such as cancer, be-cause it is believed to have antimicrobial, anticancer andantioxidant activities, and to improve immune function. Themajor constituents of garlic are organosulfur compounds (e.g.allicin and alliin), which are responsible for the suggestedbeneficial biological effects.f' '*!

In rats, potential pharmacodynamic interactions have beenreported with antihyperlipidaemia and antihypertensive medi-cines, such as atorvastatin, propranolol, hydrochlorothiazide orcaptopril.''^'^'^"^'"'^ High doses of oral atorvastatin (lOmg/kg)'have induced kidney damage if used either alone or in combi-nation with high concentrations of garlic (1% in the food), whilelow doses of atorvastatin (2.5 mg/kg) in combination with highconcentrations of garlic (0.75% in the food) had a minimalnephrotoxic potential.''^^' These results are consistent withthe antioxidant and nephroprotective properties of garlic.'^"'^Similarly, garlic homogenate 250 mg/kg either alone or withpropranolol showed a significant increase in the activity ofantioxidant enzymes during ischaemia-reperfusion myocardialdamage. However, garlic homogenate 500 mg/kg failed to providea cardioprotective effect.'' ^^ Furthermore, garlic homogenate250 mg/kg together with hydrochlorothiazide exhibited syner-gistic cardioprotective and antihypertensive properties againstfructose- and isoproterenol-induced toxicities.'''^''^^' Combinedtherapy with garlic (250 mg/kg) and captopril demonstratedeven greater synergistic antihypertensive and cardioprotectiveeffects.''^'^°°^ Indirect clinical evidence implied a potential roleof garlic-derived S-allylmercaptocysteine for improving doc-etaxel-based chemotherapy in the treatment of hormone-refractory prostate cancer.' "-^! Importantly, garlic extracts canprotect against ciclosporin-induced nephrotoxicity or hyperli-pidaemia in rats and renal transplant patients.'

2.3.1 In Vitro arid Animal Studies

Modulation of the activity and expression of CYPs is de-pendent on the type and chemical composition of garlic sup-plements and their dosage regimen.' '' • ' ^l Two studies withhuman liver microsomes demonstrated that extracts of freshand aged garlic (if stored in an ethanol solution for 20 months)could inhibit complementary DNA (cDNA)-expression ofCYP2C9, CYP2C19 and CYP3A, as well as P-gp activity, buthad no effect on CYP2D6.'^°^'2°^] Six water-soluble componentsof aged garlic extract failed to produce more than 50% inhibition ofCYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3Aeven at high concentrations (lOO^imol/L).'^"^! Exposure ofhuman hepatocytes to increasing concentrations of garlic extracts(0-200 ng/mL) revealed a concentration-dependent reduction inCYP2C9 activity and mRNA expression, but no effect on

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Drug Interactions with Herbal Medicines 87

CYP3A4 activity was seen.^'"' The diallyl disulfide in garlicoil inhibited CYP2A6 activity in a competitive/noncompeti-tive mixed manner, with an inhibition constant (Kj) value of2.13|xmol/L.PH]

Furthermore, in human K562 leukaemic cells and mouse he-patocytes, diallyl sulfide (8.75 x 10"^ mol/L) effectively inhibitedthe induced P-gp overexpression.'^'^l However, in human mul-tidrug-resistant carcinoma KB-C2 cells, diallyl sulfide and diallyltrisulfide showed no inhibitory effects on P-gp.^'^l This fmding isconsistent with a recent observation that in Caco-2 cells, garlichad no inhibitory potential on P-gp-medi.ated transport of di-goxin.P''*' Interestingly, hydrophilic sulphur compounds of gar-lic increased P-gp mediated rhodamine 123 (Rhol23) efllux,whereas the lipophilic fraction increased P-gp efflux through therat ileum but not through Caco-2 cell monolayers.P'^'-^'^l

In rats, garlic oil and its three organosulfur compounds(diallyl sulfide, diallyl disulflde and diallyl trisulfide) can in-crease the protein content and mRNA levels of CYPlAl,CYP2B1 and CYP3Al.P06.2i7] Likewise, diallyl sulfide can in-hibit CYP2E1 expression and activity.^'^l

Some in vitro interactions of ritonavir, saquinavir and dar-unavir with garlic have been demonstrated, but the results havebeen contradictory.P'^'^^^l In Caco-2 cells, allicin exhibited con-centration-dependent inhibition of ritonavir efflux. In addition,allicin inhibited CYP3A4 activity when tested with the Vivid®CYP3A4 assay kit.P'^1 As saquinavir and darunavir are boundto different binding sites on P-gp and/or multidrug resistanceassociated protein (MRP)-2, opposite in vitro interactions wereobserved. Aged garlic extracts caused significant inhibition ofsaquinavir efflux from HepG2 cells and rat liver slices, while inboth liver models, the activity of darunavir efflux transportersincreased significantly.P^°'-^^'l Moreover, aged garlic extractscan significantly elevate the efflux of saquinavir and daruna-vir from enterocytes into gastrointestinal lumen, whereas theirCYP3A4 metabolism is inhibited.'^^^' Therefore, garlic can mod-ify the hepatic and intestinal transporter-enzyme interplay,possibly leading to pharmacokinetic interactions.

2.3.2 Ciinicai Studies

Three clinical trials in healthy volunteers indicated that garlicoil may selectively inhibit CYP2E1 activity, as revealed by de-creased 6-hydroxychlorzoxazone/chlorzoxazone serum ratios.Following administration of a cocktail containing midazolam,caffeine, chlorzoxazone and debrisoquine, no effect on the activ-ity of CYP1A2, CYP2D6 or CYP3A4 is likely.' s-sv] j n 14healthy volunteers, garlic extract (1800 mg twice daily) hadno effect on the activity of CYP2D6 (dextromethorphan) andCYP3A4 (alprazolam).'^"'1 In ten women with metastatic breast

cancer, co-administration of garlic 600 mg twice daily reducedsystemic clearance of docetaxel (a CYP3A4 substrate) to 77%and 65% on days 8 and 15, respectively (p = 0.17). However, inpatients carrying a CYP3A5* 1A alíele, it cannot be excluded thatgarlic could decrease clearance of docetaxel.'^^^ Garlic extracthad no effect on CYP3A4 in human intestine and liver but in-duced intestinal expression of P-gp to 131% (95% CI 105, 163)and decreased the saquinavir AUC to 85%.^^^^ In 16 subjects,long-term administration of an aged garlic extract (approxi-mately equivalent to six or seven cloves of garlic) for 3 monthshad no effect on the pharmacokinetics of paracetamol (aceta-minophen), a drug partly metabolized by CYP2E1 .' '1

Because garlic has complex cardiovascular effects, includinganticoagulant and antiplatelet activity, it could theoreticallyinteract with anticoagulant or antiplatelet drugs.^^^^ One casereport suggested that garlic can increase the international nor-malized ratio (INR) in patients previously stabilized on war-farin.' ^1 However, co-administration of garlic (4g/day) did notsignificantly alter the pharmacokinetics or pharmacodynamicsof warfarin.f^ ' ^l Therefore, garlic extract is relative safe andposes no serious haemorrhagic risk to patients on monitoredwarfarin therapy. Another case report indicated that garliccould decrease the INR in patients receiving the anticoagulant

Garlic is commonly used by HIV-infected patients to im-prove health and to treat some opportunistic infections, and ithas the potential for interactions.'^^''! In ten healthy subjects, asignificant decline in plasma concentrations of saquinavir wasreported after administration of garlic (~8 g raw garlic/day) forover 3 weeks.'6 *1 In contrast, in ten healthy volunteers, dosing ofgarlic extract (two 5 mg capsules) taken twice daily over 4 daysdid not significantly alter the single-dose pharmacokinetics ofritonavir.'^-'] As both, saquinavir and ritonavir are substrates ofCYP3A4 and P-gp, the reason for the discrepancy is presentlyunclear. A longer duration of garlic therapy may be required inorder to observe a significant decrease in plasma concentrationsof ritonavir.

While further information in humans is awaited, caution isadvised if garlic is taken concomitantly with substrates ofCYP2E1, CYP3A4 or P-gp or with antiretroviral drugs (i.e.saquinavir and ritonavir).

2.4 Gitikgo

Ginkgo {Ginkgo biloba) is among the most popular herbalmedicines worldwide. It is used for the treatment of cerebralinsufflciency or peripheral vascular disease, and is frequentlytaken for enhancement of memory function.' ^^^ The flavonol

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Shi & Klotz

glycosides (e.g. quercetin, kaempferol and isorhamnetin) andterpene trilactones (e.g. Ginkgo bilobalides A, B and C; andbilobalide) are the major constituents of Ginkgo. Most studieshave been performed using EGb 761, a well defined extract ofG. biloba.

G. biloba has clinically relevant antipiatelet activity, andmany detailed reports of haemorrhage (usually cerebral, ocularor postsurgical) in patients using G. biloba extracts (GBE) havebeen published.'^^*1 Co-administration of G. biloba (120 mg)with either ciiostazol or clopidogrel did not enhance anti-platelet activity but did potentiate the prolongation of bleedingtime induced by ciiostazol.'^"' In contrast, studies using in vitroand in vivo models have reported that G. biloba may potentiatethe antiplateiet effect of ciiostazol without prolongation ofbleeding time or coagulation time.'^^'' Recently, in elderlypatients with peripheral artery disease, EGb 761 (300 mg/day)combined with aspirin (325 mg/day) did not have a significantimpact on coagulation examined over 4 weeks.' ^^l This result isconsistent with findings where co-administration of ace-tylsalicylic acid and EGb 761 did not constitute a safety risk.'^^^'Likewise, a clinical review indicated that Ginkgo did not sig-nificantly affect the safety of co-administered aspirin (acet-ylsalicylic acid) or

2.4.11n Vitro and Animai Studies

Several studies have indicated that various constituents ofG. biloba have different effects on CYPs. One study with human livermicrosomes indicated that GBE is a potent inhibitor of CYP1A2,CYP2C19 and CYP2C19 but did not inhibit CYP2D6 andCYP3A4.'2O»1 The flavonoidic fraction of EGb 761 showedstrong inhibition of CYPl A2, CYP2E1, CYP2C9 and CYP3A4,whereas the terpenoidic fraction inhibited only CYP2C9. Themajority of EGb 761 fractions can inhibit CYPs at low levels(concentration of drug producing 50% inhibition [IC50]<40ng/mL).'^^'' In human and rat priniary hepatocytes, GBE(100-2500 ng/mL) significantly induced the activity, proteinexpression and mRNA expression of CYP3A in a dose-depen-dent manner.'232] Similarly, GBE had minor effects on CYP2D6and caused moderate inhibition of CYP2C9, as well as mild-to-moderate inhibition of CYP3A4, depending on the substratethat was used."^'" In addition, Ginkgo can inhibit CYP2C8 at10 |imol/L but has no effect on P-gp.'^^^'

Interestingly, two separate in vitro studies indicated that ter-pene trilactones and flavonol glycosides of GBE did not sig-nificantly inhibit the activities of CYPlAl, CYP1A2, CYPIBI,CYP2C9 and CYP3A4. However, flavonol aglycones, the bi-flavonol amentoflavone and several other non-glycosidic con-

stituents were significant inhibitors of CYPs.' "*'- ^ ' The modeof inhibition is competitive, noncompetitive or mixed, depen-ding on the enzyme and flavonol tested. Modulation of CYPl Alor CYPlB1 activity or gene expression by GBE was also observedin other in vitro studies.' ^^-^^^

Recently, in cultured primary human hepatocytes, the effectsof GBE (2.19-219 ng/mL) on CYPs were evaluated."85-i88]GBE may exert opposite and biphasic effects on CYP1A2 andCYP2D6 metaboHsm. Induction of CYPl A2 and inhibition ofCYP2D6 were found at low concentrations (2.19(ig/mL); theopposite was observed at higher concentrations (219 |ig/mL).''^^Likewise, GBE (2.19-219 |xg/mL) showed an induction/inhibi-tion profile towards CYP2C19 but a weak inhibitory effect onCYP2El.''«^i It was also able to inhibit CYP2D6 or CYP3A4activity, but P-gp activity was unaffected.''^^''^^' In Caco-2monolayers, the Ginkgo flavonols quercetin, kaempferol andisorhamnetin were substrates of P-gp and appeared to inhibit orinduce P-gp activity.'^^^'

Likewise, in rats, GBE can induce or inhibit various CYPs,depending on the compositions or constituents of the GBE.' ^^" '' 'In rats that were fed a diet of 0.5% GBE over 5 days, CYPlAl,CYP1A2, CYP2B, CYP2C, CYP2E1, CYP3A4 and glu-tathione S-transferase (GST) were induced in the liver.'^'"''^'*''The inductive effect was rapidly reversible after discontinuationof GBE even after excess treatment.'-^^'^ However, addition ofGBE to rat and human hepatic microsomes can cause con-centration-dependent inhibition of various CYP activities. Be-cause of inductive effects on CYP2C, CYP2B and CYP3A,pretreatment with a 0.1% GBE diet in rats significantly affectedthe hypoglycaemic action of tolbutamide (CYP2C)'^''^' and re-duced the therapeutic potency of phénobarbital (CYP2B) andnicardipine (CYP3A4).' '*'*" '*^ In contrast, co-medication withGBE (20 mg/kg) did not affect the pharmacokinetics after in-travenous administration of the CYP3A4 substrates nifedipine(2.5 mg/kg) or ciclosporin but markedly increased the absolutebioavailability after oral administration, suggesting that GBEinhibited intestinal CYP3A4 without affecting hepatic CYP3-^ 4 [247,248] jjj addition, GBE (10 or lOOmg/kg/day) can decreasethe oral bioavailability of propranolol (10 mg/kg) and theophyl-line (10 mg/kg) [CYP1A2] because of enzyme induction.'249.250]

2.4.2 Ciinicai Studies

The effect of GBE on various CYP isoforms has been widelyinvestigated in clinical studies using different probes, such as caffeine(CYP1A2), bupropion (CYP2B6), tolbutamide (CYP2C9), diclo-fenac (CYP2C9), flurbiprofen (CYP2C9), diazepam (CYP3A4and CYP2C19), debrisoquine (CYP2D6), dextromethorphan

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Drug Interactions with Herbal Medicines 89

(CYP2D6), chiorzoxazone (CYP2E1), alprazolam (CYP3A4)or midazoiam (CYP3A4).[55,56,68,69,7i,72,75,77,79] jjj j^Q3^ studies,

GBE had no significant effect on CYP1A2, CYP2D6, CYP2E1,CYP3A4, CYP2C9, CYP2C19 or CYP2B6.' 5,56,68,69,71,72,77]

In ten healthy volunteers, GBE (360 mg/day) slightly butsignificantly decreased the AUC of tolbutamide by 16%. TheAUC of midazoiam was significantly increased (by 25%) andoral clearance was decreased (by 26%).[^'l In contrast, in oneclinical trial, GBE (120 mg twice daily for 28 days) decreased theAUC and C^^ of midazoiam by 34% (p=0.03) and 31 % (p=0.03),respectively, suggesting that GBE could induce CYP3A.t''^'O'ral ingestion of GBE (240 mg) did not significantly affect thepharmacokinetics of nifedipine, another CYP3A4 substrate.H^owever, in two subjects, the C^ax of nifedipine was approxi-mately doubled. In addition, both subjects had more severe andlonger-lasting headaches, dizziness or hot fiushes, and a trendtowards higher heart rates when GBE was co-administrated.[^°'GBE (90 mg/day for 30 days) did not have a major impact onthe pharmacokinetics and pharmacodynamics of donepezil, asubstrate of CYP2D6 and CYP3A4.'''''] EGb 761 (120 mg/dayfor 90 days) did not significantly affect the pharmacokineticproperties of metformin.'^^l

Two separate studies in healthy Chinese subjects examinedwhether the effect of GBE on CYP2C19 activity was modulated bythe CYP2C19 metabolizer status.'^''^^ Twelve days of treatmentwith GBE (120mg twice daily) did not significantly alter thepharmacokinetics of voriconazole in either extensive or poor me-tabolizers of CYP2C19.'*'^ In contrast, 12 days of treatment withGBE (140mg twice daily) induced hydroxylation of omepra-zole in a CYP2C19 genotype-dependent manner. Concurrently,renal clearance of 5-hydroxyomeprazole was reduced.'^'l Re-sults from some clinical trials in healthy subjects indicated thatGBE did not significantly affect the pharmacokinetics orpharmacodynamics of warfarin or ticlopidine.'^'*"^^'^^'

The effects of GBE on the pharmacokinetics of the P-gpsubstrates digoxin, talinolol and fexofenadine have been exam-ined in healthy volunteers.'"'''^'''^'^2,83] Q g g (120 mg twice daily

for 28 days or 80 mg three times daily for 7 days) did not have anysignificant effect on the disposition of digoxin, fexofenadine orlopinavir (a CYP3A4 and P-gp substrate).'^^'^^! However, long-term use of GBE (360 mg/day for 14 days) significantly in-creased the C^ax and AUC of talinolol, probably by inhibitionof P-gp-mediated drug efflux.t - l Likewise, in 12 healthysubjects, short-term use of quercetin (500 mg/day for 7 days)increased plasma concentrations of fexofenadine.'^^1

In summary, consumption of GBE should be monitored inpatients receiving drugs metabolized by CYP2C19, while theelïect of GBE on CYP3A4 or P-gp requires additional study.

2.5 Goldenseal

Goldenseal (Hydrastis canadensis) is one of the most popularherbs used as a topical antimicrobial. It is especially useful fordigestive disorders because of its alterative, anticatarrhal, anti-infiammatory, antimicrobial, laxative, emmenagogue and oxy-tocic properties.'^^'' Goldenseal contains various isoquinolinealkaloids: hydrastine, berberine, berberastine, hydrastinine, tetra-hydroberberastine, canadine and canalidine, of which hydrastineand berberine are the main active constituents.'^^^'

2.5.1 In Vitro and Animal Studies

Six studies have assessed the impact of goldenseal on CYPisoenzymes."*3'' '233'253-255] /„ y^^.^ goldenseal inhibited CYP2C8,CYP2C9, CYP2C19, CYP2D6 and CYP3A4.'i«3,233,253,254] B^^J^upregulation and downregulation of CYP3A4 expression wereobserved with varying concentrations of goldenseal. It appearedto have no effect on P-gp.[233,255] jjj addition, goldenseal is a stronginhibitor of CYP2E1, and the inhibition appeared to be relatedto the presence of the alkaloids berberine, hydrastine and cana-dine in the extract. These compounds inhibited CYP2E1, withK, values ranging from 2.8 |xmol/L for hydrastine to 18 ^mol/Lfor berberine.f'^'i In contrast, in rats, berberine (30 and 100 mg/kg)produced a dose-dependent increase in the bioavailability of di-goxin and ciclosporin by inhibition of intestinal P-gp, but no sig-nificant effect of berberine on CYP3A activity was observed.' ^^^

2.5.2 Clinical Studies

Three studies conducted in healthy volunteers evaluated theimpact of goldenseal on the activities of CYP3A4/5, CYP1A2,CYP2E1 and CYP2D6 by using midazoiam, caffeine, chiorzo-xazone and debrisoqtiine, respectively.''*^-'' ' ^! Goldenseal stronglyinhibited CYP2D6 and CYP3A4/5 activity, whereas no effect onCYP2E1 and CYPl A2 activity was noted. However, in ten healthysubjects, goldenseal root (1140 mg twice daily) did not signi-ficantly inñuence the pharmacokinetics of the CYP3A4 sub-strate indinavir.'^^l In 12 healthy volunteers, goldenseal (3210 mgdaily) increased the C^ax of digoxin by only 14%, indicating noimpact on P-gp activity.'^'!

Berberine markedly increased blood concentrations of ciclo-sporin in healthy volunteers given a dose of 0.3 g and in renaltransplant recipients given 0.2 g three times daily for 12 days,'^'-'"'which could be explained by inhibition of CYP3A4 in the liverand/or small intestine.

Overall, the available clinical evidence suggests that berbe-rine from goldenseal has the potential to interact with CYP3A4substrates. Goldenseal does not notably modify P-gp; thereforean interaction with digoxin is very unlikely.

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2.6 Kava

Because of its anxiolytic and sedative properties, kava (Pipermethysticum) is a popular herbal medicine used in the treatmentof anxiety, depression, insomnia and restlessness.'^^'' The activeingredients in kava root are known as kavalactones, includingkawain, dihydrokawain, methysticin, dihydromethysticin, yan-gonin and desmethoxyyangonin. Recently, concern about thehepatotoxicity of kava has been raised'^^^' and, for this reason,the herb has been withdrawn from European markets.'^^^^Additionally, the FDA has issued a safety alert about kava andits liver problems.'^^'^l Potential pharmacodynamic interactionswith alprazolam and levodopa have been also reported.'

2.6.1 In Vitro and Animal Studies

The impact of kava extracts and individual kavalactones onCYP enzymes has been investigated, using human liver micro-somes.' ^^l Whole kava extract significantly reduced the activityof CYP1A2 (56% inhibition), CYP2C9 (92%), CYP2C19 (86%),CYP2D6 (73%), CYP3A4 (78%) and CYP4A9/11 (65%), whereasno effect on CYP2A6, CYP2C8 and CYP2E1 was found. Exceptfor kawain, the major kavalactones (including desmethoxyyan-gonin, methysticin and dihydromethysticin) can inhibit CYP2C9,CYP2C19, CYP2D6 and CYP3A4. Similarly, in both cDNA-expressed human enzymes and cryopreserved human hepatocytes,the kava extract and three kavalactones (methysticin, desmeth-oxyyangonin and yangonin) were found to be potent inhibitors ofCYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4,CYP4A9 and CYP4A11.'208-263-265] j^ava also caused a dose-dependent decrease in the activity of CYP3A4, with an IC50 valueof 15.5^g/mL,'^^^ and was capable of inducing CYP3A4 viahuman PXR.'2^öl Additionally, an in vitro assessment of kavaextracts and kavalactones demonstrated that they inhibited P-gpactivity, with concentrations needed to double baseline fluores-cence values of 170 |J.g/mL and 17-90 fimol/L, respectively.'^*^

In rats, kava extract and kavalactones had some impact onCYP isoenzymes.'^^^'^'O' The kava alkaloid piper methystine wascapable of inducing CYPl A2 and CYP2E1 .'26«] A, high dose for8 days (equivalent to approximately 380 mg of kavalactones/kg/day; 100 times the suggested dosage for human use) of twodifferent types of kava products significantly increased the liverweight, CYPl A2 mRNA expression (2.8- to 7.3-fold) and CYPlAlmRNA expression (75- to 220-fold).'2*^ ' In rats, a 7-day pretreat-ment with kava extract (256 mg/kg/day) only modestly inducedhepatic CYP activity. However, in microsomes, kava can inhibitCYP2C9, CYP2C19, CYP2D6 and CYP3A4 activity in a concen-tration-dependent manner. Kj values for the inhibition of CYP2C9

and CYP2C19 activities by methysticin, dihydromethysticin anddesmethoxyyangonin ranged from 5 to 10|imol/L.' ™^ Therefore,kava has a high potential for causing pharmacokinetic interactionsat the site of drug metabolism.

2.6.2 Clinical Studies

Four studies evaluated the effect of kava (2000, 408.9 or3681 mg/day) on CYP isoenzymes.'' -'' -^-'- '' Kava could signif-icantly inhibit CYP2E1 activity but had no impact on the activitiesof CYP3A4/5, CYP1A2 or CYP2D6.' -45-53] Only one study hasshown that kava may inhibit CYP1A2 activity, but no effects onCYP2C19, CYP3A4, CYP2D6 and CYP2E1 were found.'^^'l

Twenty healthy volunteers received a standardized kavasupplement (1227 mg daily) for 14 days. No significant effectson the disposition of digoxin were observed,'''^ suggesting thatkava did not modulate the function of P-gp.

In conclusion, caution is advised if kava is taken concomitantlywith CYP2E1 substrates. There is no evidence that kava affectssubstrates of CYP2C19, CYP3A4, CYP2D6 and P-gp, but fur-ther investigations are necessary to strengthen this impression.

2.7 Milk Thistle

Milk thistle (Silybum marianum) is one of the most commonlyused herbal medicines for treatment of alcoholic liver disease,acute and chronic viral hepatitis, and toxin-induced liver diseases.Its major active constituent is a lipophilic extract from seeds,and it is composed of three isomer flavonoHgnans (silybin, sily-dianin and silychristin), collectively known as silymarin. Silybinis the component with the most pronounced biological activityand makes up 50-70% of silymarin.'2''2]

Aqueous extracts of milk thistle exhibited potent hypogly-caemic and anti-hyperglycaemic activities in normal and strep-tozotocin-induced diabetic rats.'^'^^ In type II diabetic patients,potential pharmacodynamic interactions may exist, related tothe ability of milk thistle to reduce blood sugar levels.' '*' Thusmilk thistle should be used with caution in patients receivinghypoglycaemic agents. In 59 patients with beta-thalassaemiamajor treated with desferrioxamine, combined therapy with sily-marin (140mg three times daily) was more effective than desfer-rioxamine alone in reducing serum ferritin levels. Significantimprovements in liver alkaline phosphatase and glutathione le-vels in red blood cells were also observed.'"'

2.7.1 in Vitro and Animai Studies

In vitro studies have indicated that both silymarin and sily-bin can inhibit various CYP isoenzymes (e.g. CYP2D6, CYP2E1,

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CYP3A4, CYP2C9 or CYP2C8) and uridine diphosphateglucuronosyltransferase (UGT).'2".255,275-279] silymarin andsilybin inhibited CYP2D6, CYP2E1 and CYP3A4 actiyity in adose-dependent manner.' ^^-^^^^ Silybin inactivated purified,recombinant CYP3A4 and CYP2C9 in a mechanism-basedmanner and inhibited the glucuronidation of 7-hydroxy-4-trifluo-romethylcoumarin catalysed by recombinant hepatic UGTIAI,1A6, 1A9, 2B7 and 2B15, with IC50 values of 1.4, 28, 20, 92 and75 nmol/L, respectively.' ^ ' However, in one study, silybin and itssynthetic beta-glycosides showed no interference with mRNAsand expression of CYPl A2 and CYP3A4.'28O]

Only at the high concentration of 100|xmol/L of silymarinhas more than 50% inhibition of CYP2B6, CYP2C8, CYP2C9,CYP2C19, CYP2D6, and CYP3A4 been observed, and no inhi-bition or moderate inhibition was found for CYPl A2, CYP2A6and CYP2El.[^^'i In a follow-up study with dry extract frommilk thistle, no inhibition or minor inhibition was noted for allCYPs tested at the lowest extract concentration of 1.5pg/mL.At concentrations of 15 and 150 [xg/mL, the extract significantlyinhibited CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1and CYP3A4.'^^^' However, in view of the clinically relevantplasma concentration being substantially lower than the inhi-bitory concentrations estimated in these studies, it is unlikely thatthere will be an interaction problem with silymarin. Using abaculovirus expression system or Caco-2 cells, three studies indi-cated that milk thistle had no effect on P-gp activity.'2'''233.255]

In rats, the pharmacokinetic interaction between silymarin(single doses of 50 and 100 mg/kg for intravenous and oral ad-ministration, respectively, and oral administration of 100 mg/kg •for 14 days) and oltipraz was investigated.'^^'-'^ After singleintravenous administration of both drugs together, the AUC ofunconjugated silibinin was significantly decreased (33%), butthose of conjugated and total silibinin were significantly increased(32% and 27%, respectively). However, after simultaneous oraladministration of the drugs, the AUCs of unconjugated, conju-gated and total silibinin were comparable. Silymarin did notsignificantly alter the pharmacokinetic parameters of oltipraz.Likewise, in rats, no marked effects of silymarin (0.5 g/kg) andsilibinin (0.175 and 0.35 g/kg) on the pharmacokinetics of trazo-done have been observed with normal daily

2.7.2 Clinical Studies

In healthy volunteers, the impact of milk thistle on CYP iso-forms was investigated using caffeine, debrisoquine, chiorzoxazone,midazoiam or nifedipine.''* ''* ''*^-'°'l Contrary to previousin vitro studies, milk thistle supplement had no significant effecton CYP1A2, CYP2D6, CYP2E1 or CYP3A4. Likewise, in six

cancer patients, short-term (4 days) or prolonged intake of milkthistle 200 mg three times daily for 12 days did not infiuencethe pharmacokinetic properties of irinotecan (a substrate ofCYP3A4 and UGT1A1).P8' Additionally, in 16 healthy malevolunteers, co-administration of silymarin (280 mg adminis-tered 10 hours and 1.5 hours prior to the administration ofnifedipine) did not change the absorption or the metabolism ofthe CYP3A4 substrate nifedipine.''^'l However, in 12 healthysubjects, administration of silymarin (140 mg/day for 9 days)increased clearance of metronidazole (a substrate of CYP3A4and CYP2C9) and that of its major metabohte by 30% and32%, respectively, with a concomitant decrease in the ti^, Cmaxand AUC, indicating induction of both intestinal P-gp and

In 12 healthy men of known CYP2C9 genotype (sixCYP2C9*\r\ and six CYP2C9*\n), the effects of silymarin(420 mg/day for 14 days) on the pharmacokinetics of losartanand its active metabolite E-3174 were investigated. Silymarin sig-nificantly decreased the AUC of E-3174 in both CYP2C9*\nand CYP2C9*\r7> subjects and significantly increased the AUCof losartan. The metabolic ratio of losartan was decreased inindividuals with the CYP2C9*\r\ genotype but not in those withthe CYP2C9*\ri> genotype. Thus silymarin inhibited the me-tabolism of losartan to E-3174, and the magnitude of the inter-action was dependent on the CYP2C9 genotype.''^' In eighthealthy male volunteers, silymarin (140mg three times daily for5 days) did not affect the pharmacokinetics of rosuvastatin, sug-gesting that silymarin is not a potent modulator of OATPIBI orbreast cancer resistance protein.''^-'^

Other studies have demonstrated that milk thistle did notalter the pharmacokinetics of indinavir'^^''^^ or ranitidine,''"^'indicating no significant effect on CYP3A4 and P-gp activity.Likewise, in 16 healthy subjects, milk thistle (900 mg daily for14 days) had no effect on the disposition of digoxin.'''^' In 18healthy adult men of known MDRl genotype, the effect of sily-marin (140 mg three times daily for 14 days) on the phar-macokinetics of the P-gp substrate talinolol and its associationwith MDRl C3435T genetic polymorphism were investigated.''"^!Silymarin significantly increased the C^ax of talinolol (p = 0.007),the AUC from 0 to 36 hours by 36% and the AUC from 0 hours toinfinity by 37%, and decreased oral clearance by 23% (p< 0.001).These effects were independent of the MDR genotype.

In summary, findings in humans have been contradictory,and further studies are needed to elucidate the role of milkthistle in altering drug disposition by affecting CYP1A2,CYP2D6, CYP2E1 or CYP3A4 or P-gp. Milk thistle does notaffect P-gp in humans, which is consistent with findings fromlaboratory studies.

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2.8 Panax ginseng

Panax ginseng (Asian ginseng) has been used in Eastern Asia formore than 2000 years. Ginseng, the root of P. ginseng, has diversepharmacological activities, including effects on the central nervoussystem, antineoplastic effects and immuhomodulatory effects. Itsmajor active components are ginsenosides, a group of steroidal sa-ponins, which may be responsible for ginseng-drug interactions.P^^

Potential pharmacodynamic interactions of P. ginseng withantiplatelet/anticoagulant drugs have been reported.!^^^! P. gin-seng has been shown to decrease the effect ofHowever, three clinical trials could not confirm these results.tRecently, in a patient with chronic myelogenous leukaemia, im-atinib-induced hepatotoxicity after concurrent ginseng ingestionwas reported.!^^^! It was proposed that the patient's late onsetof imatinib-associated hepatotoxicity was due to an interactionbetween ginseng and imatinib through CYP3A4.

2.8.11n Vitro and Animal Studies

Several in vitro studies have evaluated the effects of ginseng orits extract constituents on CYP isoforms.P'9.289] Ginseng caninhibit CYP2C9, CYP2C19, CYP2D6 and CYP3A4.P89] Purifiedkaempferol from ginseng has exhibited remarkable inhibition ofP-gp-mediated efflux of ritonavir and CYP3A4 activity.!^'^!

Unfortunately, the reported effects of ginseng extracts orginsenosides on CYPs have been inconsistent and even con-flicting.f^'^"^^^! The effects of seven ginsenosides and two eleu-therosides on the catalytic activity of cDNA-expressed CYPisoforms have been investigated.! ^**! Ginsenoside Rd weakly in-hibited CYP3A4 and inhibited CYP2D6, CYP2C19 and CYP2C9to an even lesser extent, while ginsenoside Re and Rf increasedCYP2C9 and CYP3A4 activity. Ginsenosides Rbl, Rb2, Reand Rgl did not significantly affect CYP1A2, CYP2C9,CYP2C19, CYP2D6 and CYP3A4 activity.P^o] However, inanother study, ginsenosides Rd and Rb2 inhibited CYP2C19and CYP2D6 activity. For CYP2C19, the IC50 values were 46and 62|xmol/L for ginsenoside Rd and ginsenoside Rb2, re-spectively, whereas only ginsenoside Rd had an IC50 value of57 mol/L for CYP2D6.I2911 Additionally, standardized P. gin-seng extract decreased the 7-ethoxyresorufm 0-dealkylationactivities of human CYPlAl, CYP1A2 and CYP'lBl, but gin-senosides Rbl, Rb2, Re, Rd, Re, Rf and Rgl had no significanteffects.t^^^! Interestingly, the naturally occurring ginsenosidesexhibited no inhibition or only weak inhibition of humanCYP3A4, CYP2D6, CYP2C9, CYP2A6 and CYP1A2 activ-ities, but their main intestinal metabolites (compound K [C-K],protopanaxadiol and protopanaxatriol) demonstrated a widerange of inhibition of CYP-mediated drug

Recently, the inhibitory effects of 15 ginsenosides and sa-pogenins on human CYP1A2, CYP2C9, CYP2C19, CYP2D6and CYP3A4 enzymes were evaluated by using commerciallyavailable fluorescent probes.t '"*! Ginsenosides Rg3 and C-Khad moderate inhibitory effects on CYP1A2, while ginseno-sides Rg3, Rh2 and C-K and all sapogenins exhibited moderateinhibition on CYP2C19 and more potent inhibition of CYP2C9and CYP3A4. Ginsenoside Rbl, Re and Rgl had no significanteffects on the activity of flve CYPs, with the exception that Rblmoderately inhibited CYP1A2.

In rats, P. ginseng extracts (4% [w/w] total ginsenosides; 30 or100 mg/kg/day for 1 or 4 days) did not increase hepatic CYP2B1,CYP3A23 or CYP1A2 gene expression.!^^^] in addition,P. ginseng (150 mg/kg/day) for 14 days decreased the AUC from0 to 12 hours of oral fexofenadine by 51% (p < 0.005), decreasedthe Cmax by 75% (p < 0.001) and significantly reduced the ratiosof brain to plasma concentrations (p<0.05). Therefore, long-term administration of P. ginseng might induce the expressionof both intestinal and brain endothelium P-g

2.8.2 Clinical Studies

In healthy volunteers, P. ginseng (1500 mg/day) had no effecton CYP3A4, CYPl A2, CYP2E1 and CYP2D6 when midazolam,caffeine, chlorzoxazone and debrisoquine were used.!^^'^^!In the elderly (mean age 67 years), P. ginseng weakly in-hibited CYP2D6 activity, but the magnitude of the effect (ap-proximately 7%) did not appear to be clinically relevant.t^^' Inaddition, P. ginseng increased plasma concentrations of nifedi-pine at 0.5 hours; however, data on additional time points werenot provided.t'"^! So far, no clinical studies have been carried outto assess the impact of ginseng on P-gp. Therefore, the availableclinical evidence suggests that the potential for ginseng-druginteractions is low.

2.9 Panax quinquefolius

Panax quinquefolius (American ginseng) has been reported tohave a wide range of pharmacological effects on the cardio-vascular and central nervous systems, antidiabetes effects, anti-tumour activities and immunomodulatory effects similar to thoseof P. ginseng.^'^^^^ Ginsenosides are also its major biologicallyactive constituents. Chemically, severaL differences exist be-tween P. quinquefolius and P. ginseng. An important parameterused for the differentiation is the presence of ginsenoside Rfin P. ginseng versus the presence of pseudoginsenoside F l l inP. quinquefolius.^-^^^'-^^^^

Compared with the long history of use and the widespreadresearch on P. ginseng, the data on P. quinquefolius are relative

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Dirug Interactions with Herbal Medicines 93

limited. In 32 healthy young adults, enhancement of the robustworking memory has been observed following administrationof three doses (100, 200 or 400 mg) oí P. quinquefoHus.^^^'^^ Theseeffects are distinct from those of P. ginseng and suggest that thepsychopharmacological properties depend critically on the gin-senoside profiles. Another clinical trial conducted in 20 healthypatients found that P. quinquefoHus reduced the anticoagulanteffect of warfarin after 2 weeks of ginseng administration.'""'

2.9.1 Animal Studies

In rats, P. quinquefoHus extracts (10% [w/w] total ginsenosides;100 or 400 mg/kg/day for 21 days) did not affect body weight gain;absolute or relative liver weight; hepatic mRNA expression ofCYP2B1, CYP3A23, or CYPl A2; microsomal CYP2B-mediated7-benzyloxyresorufin 0-dealkylation; or CYPlA-mediated 7-eth-oxyresorufin O-dealkylation.'^'^'

2.9.2 Clinical Studies

In 13 healthy volunteers receiving indinavir 800 mg every8 hours for 3 days and then indinavir and P. quinquefoHus 1 g every8 hours for 14 days, the potential interactions between bothagents was tested,''"^' Indinavir can decrease insulin sensitivity,which was unaltered by P. quinquefoHus co-administration.P. quinquefoHus did not significantly affect the pharmacokineticsof indinavir. Another study in ten healthy volunteers showedthat intake oí P. quinquefoHus 200 mg twice daily for 2 weeks didnot alter the pharmacokinetics of zidovudine but did reduceoxidative stress markers.'"'^ In summary, the available clinicalevidence suggests that the potential for P. quinquefolius-drug in-teractions is low.

2,10 Saw Palmetto

Saw palmetto {Serenoa repens) is one of the most widely usedherbal preparations for the treatment of lower urinary tractsj'mptoms and benign prostatic hyperplasia.'^*'"' Eatty acidsand sterols are two active fractions of saw palmetto. A recentreview suggested that adverse events associated with the use ofsaw palmetto are mild, and no evidence for drug interactionswith saw palmetto have been reported,'^°'^

2.10.1 In Vitro and Laboratory Studies

One in vitro study indicated that saw palmetto showed potentinhibition of the activities of CYP3A4, CYP2D6 and CYP2C9,'' '*1suggesting the potential for drug interactions. Therefore, patientsshould be encouraged to inform their physicians when using thisherb, and physicians should advise patients of potential risks ifherbal medicines are combined with prescription medications.

2.10.2 Ciinicai Studies

Results in humans have been inconsistent with data from clin-ical studies. In 12 healthy volunteers, saw palmetto (320 mg/day for28 days) had no significant effect on CYPl A2, CYP2D6, CYP2E1and CYP3A4 activity when caffeine, debrisoquine, chlorzoxazoneand midazolam were used,''* ' Use of saw palmetto (320 mg/dayfor 14 days) had similar effects on the activities of CYP2D6 orCYP3A4 when the probes dextromethorphan and alprazolamwere used.'"^' Therefore, botanical supplements containing sawpalmetto extracts appear to pose a minimal risk of CYP-mediatedinteractions.

2.11 St John's Wort

St John's wort (SJW; Hypericum perforatum), one of the oldestand best investigated herbal medicines, is the most commonlyused herbal antidepressant for treatment of mild to moderatedepression,[ '' •^"^1 SJW contains numerous pharmacologicallyactive compounds, including naphthodianthrones (e.g. hyper-icin and pseudohypericin), phloroglucinols (e.g. hyperforin andadhyperforin) and fiavonoids (e.g. quercetin, quercitrin and 13,118-biapigenin).'^'''*' Given the widespread use of SJW, a majorsafety concern is its ability to alter the pharmacokinetics and/or clinical response of a variety of clinically important drugs.Several comprehensive reviews have already focused on SJW-drug interactions.'-'"^"-'^''

Potential pharmacodynamic interactions resulting in serotoninsyndrome can occur when SJW is used with other serotonergicdrugs, as a result of additive serotonin effects or inhibition ofdrug metabolism.f"'''^^'-""' An interaction has been observedbetween SJW (300 mg twice daily for 4 weeks) and atorvastatinin patients with hypercholesterolaemia.'"^' SJW can sig-nificantly increase the serum levels of low-density lipoproteinand total cholesterol, suggesting a need to increase the doseof atorvastatin when co-administration of SJW is necessary. Inaddition, SJW (300 mg three times daily for 14 days) enhancedthe antiplatelet effect of clopidogrel in hyporesponsive volun-teers and patients.'^"'

2.11.1 In Vitro and Animal Studies

In vitro studies have suggested that SJW extracts can inhibitCYP3A4, CYP2C9, CYP1A2, CYP2D6, CYP2C19 andCYP IB I.'24.'83.208,312,313] Importantly, individual constituentsof SJW have different inhibitory effects on CYP isoenzymes.Hyperforin is a potent, noncompetitive inhibitor of CYP2D6(K¡ value 1.5nmol/L) and a competitive inhibitor of CYP2C9and CYP3A4 (K; values 1.8 and 0.48 nmol/L, respectively).13,118-biapigenin is a potent, competitive inhibitor of CYP3A4,

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94 Shi &• Klotz

CYP2C9 and CYPl A2 (K; values 0.038, 0.32 and 0.respectively), and hypericin is a potent inhibitor of several CYPactivities.' "*' Seven flavonoids (myricetin, apigenin, kaempferol,quercetin, amentoflayone, quercitrin and rutin) are slightlymore selective for CYPIBI inhibition (K; value 0.06-5.96 |imol/L)than for CYPlAl inhibition (K; value 0.20-1.6 ^imol/L), where-as rutin has no inhibitory effect on CYPlAl. Apigenin and amen-toflavone are competitive inhibitors of CYPIBI, while quercetinshows mixed-type inhibition.'^'-''

However, most in vitro studies have demonstrated that SJWextracts can result in significant induction of CYP3A4.''^^'^''*"^'^'The magnitude of CYP3A4 induction correlated significantlywith the content of hyperforin in the SJW extracts but not withthe content of flavonoids or hypericin.'^'''•^'^' Induction ofCYP3A4 by hyperforin is mediated by PXR.'^''*-^'^' In contrast,in human hepatocytes, acute administration of hyperforin at 5and 10 (imol/L 1 hour before and together with probe substratesinhibited CYP3A4 activity.'^'5' Additionally, SJW showed dose-dependent induction/inhibition effects against CYP2C19 andCYP2E1, with induction at low doses (8 ng/mL) and inhibitionat higher doses (800 g/mL)."^""

Likewise, studies in mice indicated that both CYP3A andCYP2E1 activities are increased 2-fold by SJW (140 or 280 mg/kg/day) but only following 3 weeks of administration.'^'^' Fourdays of treatment with moderate to high doses of SJW (435 mg/kg/day), hyperforin (1 mg/kg/day) or hypericin (10 mg/kg/day)failed to induce the activities of CYPl A2, CYP2E1 and CYP3-^ [320] jj^ mice, hyperforin also played a key role in the inductionof CYP3A.'^^'' In rats, pharmacokinetic interactions betweenSJW (150 or 300 mg/day for 15 days) and indinavir have beenobserved and were due to CYP3A4 induction.'^^^' SJW adminis-tration (100 mg/kg/day for 10 days) in rats resulted in significantinduction of CYP2D2 and CYP3A2 and signiflcant inhibition ofCYP2C6.'323] Administration of SJW extract to rats for 14 daysincreased intestinal P-gp/MDRl expression 3.8-fold and hepaticexpression of CYP3A2 2.5-fold."3°' In rats, SJW (400 mg/kg/dayfor 10 days) also led to overexpression of hepatic MRP2, GST-Pand CYP1A2.'324] Interestingly, SJW (100 and 1000 mg/kg/day)signiflcantly decreased transcripts of MDRla, MDRlb, MRPl,MRP2 and CYP3A2 genes in the livers of fetuses and increasedhepatic levels in the mothers.'^^^'

Several in vitro studies have shown that only long-term ad-ministration of SJW and hyperforin strongly induces p.gp [326-330]and no acute effects on P-gp activity have been observed.'-'^''Induction of P-gp by SJW can be mainly attributed to hyperforin,but other constituents (e.g. hypericin or quercetin) may also havesome inductory effect.' ^ ' ^*' ^"' In an in vitro/ex vivo blood-brain barrier model, the short-term effects of SJW extract and

its constituents (hyperforin, hypericin and quercetin) on theblood-brain barrier function of P-gp were studied.'^^'' SJW extract(0.1-5 |ig/mL) and its constituents hyperforin (0.1-10 imol/L),hypericin (1-50 |xmol/L) and quercetin (l-50ixmol/L) decreasedP-gp activity in a dose- and time-dependent manner. SJW andhyperforin directly inhibited P-gp activity, whereas hypericin andquercetin modulated the transporter function through a mechan-ism involving protein kinase C. At high concentrations (10 ^imol/L),quercetin decreased P-gp activity, but at low concentrations(l-lO^imol/L), it increased its function.

2.11.2 Ciinicai Studies

The effects of SJW on CYP isoenzymes have been widelyevaluated using probes such as midazolam, alprazolam, nifedi-pine and erythromycin for CYP3A4, tolbutamide for CYP2C9,caffeine for CYP1A2, dextromethorphan and debrisoquine forCYP2D6, chlorzoxazone for CYP2E1 and omeprazole forCYP2C19.'''5.55,56,l 15,120-122,125,129,130,146,148,152,153] SJYV? (900 m g / d a y

for 14 days) significantly induced the activity of CYP3A4, CYP2E1and CYP2C19, whereas no effects on CYP2C9, CYP1A2 orCYP2D6 were observed. CYP1A2 appeared to be induced bySJW only in females.''^°' Importantly, there is considerably lessinduction of CYP3A after intravenous administration of theprobes than after oral administration, suggesting that the pri-mary site of action of SJW is intestinal rather than hepat-¿(, [121,125,130] Oral clearance of midazolam was signiflcantlyincreased after administration of St John's wort (300 mg threetimes daily for 14 days), and CYP3A-induced activity pro-gressively returned to basal levels approximately 1 week aftercompletion of SJW treatment.'"*^'

Likewise, a few clinical trials have demonstrated an inductiveeffect of SJW on P-gp. Plasma concentrations and AUCs ofwell known P-gp substrates (including digoxin,'^'•'^°"'^^' fexofe-nadine''25.133,134] and talinolol''^^]) jjave been reduced by SJW.

Hyperforin, but not hypericin, appears to be the key activator ofPXR, resulting in induction of CYP3A4, P-gp and several otherenzymes.'' ' *®' ' ' ^ ' Consistent with in vitro and animals findings,SJW extracts with a low hyperforin content have not demonstratedany clinically relevant interactions."'3''26.i46,i47,i54,305,309,333]

Furthermore, short-term (1-3 days) administration of SJW didnot induce CYP3A4 or P-gp, and longer treatment is generallyrequired to show the inductive effect.""''"5.i2i,i25,i33,i68,i69]

Interestingly, induction of CYP3A and P-gp activity by SJW(300 mg three times daily for 10 days) was comparable in healthyvolunteers from six ethnic populations - namely, Caucasians,African Americans, Hispanics, Chinese, Indians and Malays."^**'

A variety of clinically significant interactions between SJWand conventional drugs have been identified, and the results

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Dmg Interactions with Herbal Medicines 95

have sometimes been contradictory, such as with the anticanceragents imatinib''^'"''"' and irinotecan;''"*^! the anti-HIV agents in-dinavir,''''^! nevirapine''^*'-'^'' and ritonavir;''^^! the antimicrobialagent voriconazoie;''^*-'^'' the cardiovasctilar drugs digoxin,' '-'-'""' 'ivabradine,""'''! warfarin,''"*! verapamil,''*^! nifedipine''^^' andtalinolol;''*-'! the central nervous system agents mephenytoin,''^^!amitriptyline,'"*! buspirone,'"^! methadone,''"*^! bupropion,'"^!midazolam,'55-56.i2i,i25,i46-i48,i62]aiprazolam,"'5! quazepam,"*'!carbamazepine''^'*! and zolpidem;"^°! the digestive system agentsomeprazole''^^! and cimetidine;''^'*! the genito-urinary systemdirug finasteride;''-'^' the hypoglycaemic agent gliclazide;''^^ theimmunosuppressants ciclosporin''25-128] ^j^^ tacrolimus;''"*'-'*"*!oral contraceptives;''^^"'^*' the respiratory system agents theo-phyliine''*^! and fexofenadine;''^^-'^^•'^''! and the statins ator-vastatin'"^ and simvastatin.''5'! Meanwhile, some results indicatedno clinically relevant interactions for co-administration of SJW withthe following conventional drugs: tolbutamide,'"^-'^'' oral con-traceptives,''^"*! ibuprofen,''^^' mycophenolic acid,'''*'' theophyl-iine,''**! pravastatin,''5'! carbamazepine''^-'! and prednisone.''*°!

In summary, a large number of studies have indicated thatS.rW can cause both pharmacokinetic and pharmacodynamicinteractions. The clinical implications of such SJW-drug inter-actions depend on a variety of factors such as the duration,dosage and therapeutic range of the treatment. Hyperforin isresponsible for some of the effects on CYP and P-gp. The potentialfor SJW-drug interactions is high; therefore, patients taking pre-scribed drugs should be discouraged from taking herbal productscontaining SJW.

3. Conclusions

Experimental and clinical data have documented that herbalmedicines can cause pharmacokinetic and/or pharmacodynamicinteractions with conventional drugs. There is accumulating evi-dence that the underlying mechanisms of the observed alterationsin drug effects and/or concentrations caused by concomitantherbal medicines are similar to classical drug interactions. In vitroand animal studies have been widely used in attempts to predictpotential drug interactions with herbal medicine. However, dis-crepancies between results of in vitro or animal studies and thoseof human studies have been observed quite often.' '*- ^5! Never-theless, caution must be exercised both in the absence of clinicaldata and with regard to reliance on lab-based evidence.

The clinical implications of any drug interaction depend ona variety of factors, such as co-administered drugs, the healthstatus of the patients, the composition of the herbal medicineand the applied dosage regimens. If a drug with a narrow the-rapeutic index (e.g. warfarin or ciclosporin) is involved, the

interactions may cause serious or occasionally life-threateningadverse effects. In addition, herbal medicine-drug interactions inhumans are likely to be highly variable because of interindividualdifferences in nutrition habits, age, sex, genetic make-up andmetabolizing capacity. Although there is an increase in theavailable information on herbal medicine-drug interactions,limited data on the pharmacodynamics and pharmacokineticsof herbal medicines and their complex structure result in diffi-culties in characterizing and predicting interactions, as well asin understanding the mechanisms. The study of herbal medi-cine-drug interactions is further complicated by the nature ofthe herbal medicine. As the manufacturing properties of herbalmedicines are not strictly standardized or regulated, the in-gredients identified on the labels of these products might beincomplete or incorrect, and the composition could be variablefrom batch to batch. Although herbal medicine-drug interac-tions have been reported in several clinical studies, it is some-times diffictilt to generalize, as the effects may be ingredientspecific.'^^^! It is proposed that the same rigorous regulationsthat apply to conventional drugs with regard to quality, safetyand efficacy should apply to herbal medicines. There is a clearneed for well designed clinical trials, pre-marketing approval re-garding labelling and safety, and comprehensive post-marketingsurveillance systems for monitoring the adverse effects of herbsand herbal medicine-drug interactions. For example, accordingto the German Commission E Monographs, a few pharmaco-logically potent herbs must be avoided in the presence of certainmedical conditions. If they do not meet the Commission EMonograph guidelines, they will not be marketed in Germany.On 30 October 2005, a new Traditional Herbal Medicines Re-gistration Scheme was introduced in the United Kingdom, whichis a requirement of the European Directive on Traditional HerbalMedicinal Products.'^^*' As stipulated by the EU Directive,'"*!a large number of herbal medicines that are currently on theEuropean market must be submitted to a registration procedure.

Although the use of herbal medicine may not be dangerousper se, lack of communication between patients and health careproviders may alter clinical management during co-administration.Patients should be encouraged to tell their health care providerswhich herbal medicines they are taking, and the health careproviders should be sufficiently informed to provide usefuladvice for their patients. Collecting such information is critical,particularly in elderly patients who are at higher risk of adverseinteractions, especially as polypharmacy is often applied in thispopulation.'•'•'^"^''°! Thus, increased knowledge of herbal medi-cine-drug interactions would enable health care providers andpatients to be alert to the potential of interactions. This wouldalso help to reduce the risk associated with any drug intake.

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96 Shi & Klotz

Finally, herbal medicines should be appropriately and compre-

hensively labelled, including the potential for drug interactions.

Acknowledgements

This work was supported by the Natural Science Foundation of HubeiProvince (P.R. China) [grant no. 2009CDB380], the Fundamental ResearchFunds for the Central Universities (P.R. China) [grant no. 2011JC039] andthe Robert Bosch Foundation (Stuttgart, Germany).

The authors declare no conflicts of interest.

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Correspondence: Prof. Dr Ulrich Klotz, Dr Margarete Fischer-Bosch Institutfür Klinische Pharmalcologie, Auerbachstraße 112,70376 Stuttgart, Germany.E-mail: [email protected]

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