glucuronidation, sulfation, and pharmacokinetics of ... · outline • a renewed interest in...
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GLUCURONIDATION, SULFATION, AND PHARMACOKINETICS OF CONJUGATED METABOLITES
Swati NagarApril 18, 2013NJDMDG, Somerset NJ
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Outline• A renewed interest in xenobiotic conjugation
• FDA guidelines• Poor IVIVE of conjugation and prediction of DDI
• Resveratrol as a model substrate• Tissue-specific glucuronidation and sulfation• Possibly active metabolites, pharmacogenetics• Auto-induction of glucuronidation
• Pharmacokinetics of resveratrol and its conjugates• Simple compartmental modeling• Incorporation of transporters
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Why evaluate metabolite kinetics?
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Metabolite disposition• Active metabolites
• Enzyme regulation • Enzyme inhibition• Enzyme induction• Genetic polymorphisms
• Complex disposition• Reversible metabolism and enterohepatic recycling• Interplay between DMEs and transporters
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UGT cellular location and orientation
Reference: Rowland, Int J Biochem Cell Biol 2013, 45:1121–32.
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Glucuronidation and DDIs• Much evidence in vitro for both UGT inhibition and
induction
• Not many clinical studies
• Complicating factors• In vitro protocols not standardized across labs• Overlapping substrate specificity, compensatory mechanisms• In vivo inhibitor concentrations below their Ki• Therefore, AUCi/AUC not as dramatic as with CYPs
References: Kiang et al, Pharmacol Therap 2005, 106:97-132.Miners et al, Biochem Pharmacol 2006, 71: 1531-39.
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UGT2B7 inhibition – fluconazole and AZT• In HIV-infected males (n=12), fluconazole significantly
decreased CL/F of AZT, and increased formation of AZT-G
• AUCi/AUC=1.92
• Sahai et al, J Infect Disease 1994, 169, 1103-7.
• IVIVE was possible when using a Ki estimate with either HLM or UGT2B7 (with BSA)
• Uchaipichat et al, Br J Clin Pharmacol 2006, 61, 427-439.
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UGT1A1 and irinotecan
References:Ando et al, Ann Oncol 1998, 9: 845-7. Desai et al, Oncogene 2003, 22:6621–28.
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UGT1A4 and lamotrigine
L48V, exon 1Reference:Gulcebi et al, Epilepsy Res 2011, 95: 1-8.
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UGT2B17 and MK-7246
Reference:Wang et al, CPT 2012, 92: 96-102.
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Outline• A renewed interest in xenobiotic conjugation
• FDA guidelines• Poor IVIVE of conjugation and prediction of DDI
• Resveratrol as a model substrate• Tissue-specific glucuronidation and sulfation• Possibly active metabolites, pharmacogenetics• Auto-induction of glucuronidation
• Pharmacokinetics of resveratrol and its conjugates• Simple compartmental modeling• Incorporation of transporters
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Resveratrol as a model substrate• Substrate for glucuronidation
• Substrate for sulfation
• Possible transporter involvement
• Possibly active metabolites
• Possible role in DME regulation
• Human studies indicate poor F
• Potential chemopreventive
• High profile research on its anti-cancer and anti-obesity potential
• NIH programmatic interest• Hope of $$
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SULT1A1SULT1E1
UGT1A1UGT1A9UGT1A7UGT1A10
References: Aumont et al, Arch Biochem Biophys 2001; 393: 281 – 289.Miksits et al, Xenobiotica 2005; 35: 1101-19.Brill et al, Pharm Pharmacol 2006; 58: 469 – 479.Sabolovic et al, Biopharm Drug Dispos 2006; 27: 181 – 189.Nagar et al, Mol Pharmacol 2006; 69: 2084 – 2092.
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Tissue-specific RES conjugationHLM HIM
ConjugationProduct
Protein Source
Vmax Km Ki Type of Fit Goodnessof Fit (r2)
R3G HLM 7.4 ± 0.25 280.4 ± 21.6 1022 ± 71.5 PSI 0.91
HIM 12.2 ± 0.34 505.4 ± 29.4ª 600.8 ± 20.5a PSI 0.95
R4’G HLM Vmax1 = 0.45 ± 0.01Vmax2 = 1.3 ± 0.03
Km1 = 65.2 ± 29 Km2 = 1685 ±106.8
na BPM 0.96
HIM 8.9 ± 0.14 454.5 ± 21.8 564.3 ± 38.1 PSI 0.95
Reference: Iwuchukwu and Nagar, DMD 2008; 36: 322 – 330.
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RES is conjugated in the lung – in vitro
Conjugation product
Protein source
Vmax(pmol/min/mg) Km (uM) Ki (uM)
Goodness of Fit
(r2)Type of Fit
R3G Mouse lung S9 324.40 ± 13.05 7.34 ± 1.60 6632 ± 1198 0.93 Partial substrate inhibition
R3S Mouse lung S9 7.05 ± 0.28 2.69 ± 0.45 2021 ± 717.6 0.96 Partial substrate inhibition
R3S Human lung S9 16.15 ± 0.48 4.45 ± 0.79 23238 ± 7305 0.95 Partial substrate inhibition
Reference: Sharan and Nagar, DMD 2013, 41: 1163 – 69.
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RES conjugation in the lung – in vivo
RES RES 15 mg/kg i.a. (n = 5)
RES 15 mg/kg i.v. (n = 5) Units
AUC0-inf 591.08 ± 167.29 294.98 ± 137.87* min*uM
Cl 118.77 ± 33.36 280.04 ± 158.25 mL/min/kg
Vss 37.59 ± 23.70 34.90 ± 20.10 L/kg
t1/2 190.58 ± 69.65 101.30 ± 43.41* min
R3G
AUC0-inf 921.23 ± 457.07 2268.35 ± 517.00* min*uM
R3S
AUC0-inf 174.94 ± 45.75 157.21 ± 77.77 min*uM
Reference: Sharan and Nagar, DMD 2013, 41: 1163 – 69.
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Implications of tissue-specific conjugation• IVIVE of clearance needs to incorporate extrahepatic
tissue metabolism
• Local tissue levels of active metabolites• Colorectal cancer chemoprevention• Lung cancer chemoprevention
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RES induces UGT1A1 transcription
Reference: Iwuchukwu et al, Life Sci 2011, 88: 1047 – 54.
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High variability in trans-resveratrol glucuronidationa human liver bank
Variability not explained by UGT1A1 TA repeat polymorphism
Reference: Iwuchukwu et al, DMD 2009; 37: 1726 - 1732
Human variability in RES glucuronidation
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Active metabolites of RES
Reference: Calamini et al, Biochem J 2010; 429: 273-282.
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Anti-estrogenic activity of R3S
Reference: Ruotolo et al, Nutr Metab Cardiovasc Disease 2013; epub.
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Colorectal cell death by RES metabolites
Reference: Aires et al, Mol Nutr Food Res 2013; epub.
Cell antiproliferativeactivity of R3S
S-phase arrest
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Outline• A renewed interest in xenobiotic conjugation
• FDA guidelines• Poor IVIVE of conjugation and prediction of DDI
• Resveratrol as a model substrate• Tissue-specific glucuronidation and sulfation• Possibly active metabolites, pharmacogenetics• Auto-induction of glucuronidation
• Pharmacokinetics of resveratrol and its conjugates• Simple compartmental modeling• Incorporation of transporters
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Trans-resveratrol Monoglucuronide 1
Monoglucuronide 2 3-sulfate
Reference: Boocock et al, Cancer Epidemiol Biomarkers Prev 2007; 16: 1246 – 1252
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Mouse PK study design
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C57BL/6J black male mouse
Right carotid artery was cannulated and 20 uL blood serially sampled
Sampling time points 2.5, 5, 10, 15, 45, 90, 180, 300, 420, 600 min & 24 hrs
Oral, intravenous (I.V.) and intra arterial (I.A.) dosing was performed
Blood samples were centrifuged at 14000 rpm for 2 minutes and plasma samples analyzed with LC-MSn
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0.001
0.010
0.100
1.000
10.000
100.000
0 200 400 600 800 1000 1200 1400 1600
Concen
tration (uM)
Time (min)
RES 15 mg/Kg i.a.
1Vc3 2
K1,2
K2,1
K1,3
K3,1
K1,0
Reference: Sharan et al, DMD 2012, 40: 1993-2001.
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R3S 5 mg/Kg i.a.
1VC, R3S
2K1,2, R3S
K2,1, R3S
K1,0, R3S
0.001
0.010
0.100
1.000
10.000
100.000
1000.000
0 100 200 300 400 500 600
Concen
tration (uM)
Time (min)
Reference: Sharan et al, DMD 2012, 40: 1993-2001.
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R3G 3.5 mg/Kg i.a.
1VC, R3G
3 2K1,2, R3G
K2,1, R3G
K3,1, R3G
K1,0, R3GK1,3, R3G
Delay Comp
0.001
0.01
0.1
1
10
100
1000
0 200 400 600 800 1000 1200 1400 1600
Concen
tration (uM)
Time (min)
Reference: Sharan et al, DMD 2012, 40: 1993-2001.
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In vivo formed versus preformed metabolites
• Different barriers to tissue access• Zonal expression of metabolizing enzymes in the organ (not every
organ is well-stirred)• Complex metabolism (e.g. sequential metabolism)• Different exposure to drug transporters
29
LiverIntestine
Reference: Pang KS, Chem Biol Interact. 2009,179:45-59.
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Reference: Sharan et al, DMD 2012, 40: 1993-2001.
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Parameters In-vivo formed metabolite
Preformed Metabolite
Cl,R3G (ml/min/Kg) 67.86 13.78 ± 5.75
Cl,R3S (ml/min/Kg) 313.08 76.29 ± 37.07
fm, R3G (%) 52.00 17.08
fm,R3S (%) 48.00 16.87
Reference: Sharan et al, DMD 2012, 40: 1993-2001.
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Simulating UGT inhibition
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
0 50 100 150 200 250
R3G
con
cent
ratio
n (u
M)
Time (min)
Simulated R3G profiles
Baseline
UGT inhibition
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Simulating SULT inhibition
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 50 100 150 200 250
R3S
con
cnet
ratio
n (u
M)
Time (min)
Simulated R3S profiles
Baseline
SULT inhibition
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Simulating UGT induction (plus MRP2 induction)
0
0.5
1
1.5
2
2.5
3
3.5
4
0 50 100 150 200 250
R3G
con
cent
ratio
n (u
M)
Time (min)
Simulated R3G profiles
Baseline
UGT induction
UGT MRP2 induction
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Simulating UGT induction (plus MRP2 induction)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 50 100 150 200 250
R3S
con
cent
ratio
n (u
M)
Time (min)
Simulated R3S profiles
Baseline
UGT induction
UGT MRP2 induction
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Summary• Xenobiotic conjugation can be complicated by issues
such as reversible metabolism, enterohepatic recycling, enzyme orientation in the cell, and interplay with transporters
• Standardized in vitro techniques, and tools like specific substrates/inhibitors/antibodies are needed
• Regulation of UGTs and genetic polymorphisms can alter the extent of clinical DDIs
• Interplay of conjugation and transport is important• Compartmental modeling can provide a step toward
predicting alterations in systemic drug and conjugated metabolite exposure
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Future directions• Single versus multiple dosing
• Time-dependent UGT induction
• Combination dosing• Interaction between combinations of UGT substrates and inducers• Comparison between synthetic phytochemicals and dietary
components• Prediction of food- and herb- drug interactions
• Transporter-UGT interactions• Clearance of conjugated metabolites• Common regulatory pathways
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Acknowledgment• Nagar Lab
• Otito Iwuchukwu, PhD• Satish Sharan, PhD• Amir Youssef• Vaishnavi Ganti• Aneesh Argikar• Priyanka Kulkarni
• Funding• NIH R03CA133943• NIH R03CA159389• NIH R01GM104178
• Collaborators• Upendra Argikar• Dan Canney• Ken Korzekwa• Henry Parkman• Ellen Walker
• Absorption Systems