Understanding the transport properties of metabolites: Case studies and considerations for drug development

Drug Metabolism and Disposition

Volumn 42, Issue 4, 2014, Pages 650-664

  Zamek Gliszczynski, Maciej J ^a   Chu, Xiaoyan ^b   Polli, Joseph W ^c   Paine, Mary F ^d   Galetin, Aleksandra ^e  

^a ELI LILLY AND COMPANY   (United States)

^b MERCK RESEARCH LABORATORIES   (United States)

^c GLAXOSMITHKLINE   (United States)

^d WASHINGTON STATE UNIVERSITY   (United States)

^e UNIVERSITY OF MANCHESTER   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

BREAST CANCER RESISTANCE PROTEIN; CARBOXYLESTERASE; CYCLOSPORIN; CYTOCHROME P450 3A; DRUG METABOLITE; DRUG METABOLIZING ENZYME; ETHINYLESTRADIOL; EZETIMIBE; FALDAPREVIR; FIRTECAN; GEMFIBROZIL; GLUCURONIDE; GLUCURONOSYLTRANSFERASE; GLUCURONOSYLTRANSFERASE 1A1; IRINOTECAN; MORPHINE; MORPHINE 6 GLUCURONIDE; MULTIDRUG RESISTANCE ASSOCIATED PROTEIN 2; MULTIDRUG RESISTANCE ASSOCIATED PROTEIN 3; MULTIDRUG RESISTANCE ASSOCIATED PROTEIN 4; MULTIDRUG RESISTANCE PROTEIN; MYCOPHENOLIC ACID; PROBENECID; SOLUTE CARRIER ORGANIC ANION TRANSPORTER 1B1; SOLUTE CARRIER ORGANIC ANION TRANSPORTER 1B3; SULFOTRANSFERASE; TACROLIMUS; TRABECTEDIN; TROGLITAZONE; UNINDEXED DRUG;

BILIARY EXCRETION; CASE STUDY; DETOXIFICATION; DIAGNOSTIC TEST; DRUG DEVELOPMENT; DRUG DISPOSITION; DRUG EFFICACY; DRUG EXPOSURE; DRUG GLUCURONIDATION; DRUG INTERACTION; DRUG METABOLISM; DRUG SAFETY; DRUG SULFATION; DRUG UPTAKE; ENTEROHEPATIC CIRCULATION; KIDNEY CLEARANCE; KIDNEY TUBULE EXCRETION; LIVER; MASS SPECTROMETRY; METABOLIC REGULATION; NONHUMAN; PRIORITY JOURNAL; PROTEIN FUNCTION; SHORT SURVEY; STRUCTURE ACTIVITY RELATION;

CARRIER PROTEINS; CYTOCHROME P-450 ENZYME SYSTEM; DRUG DISCOVERY; DRUG INTERACTIONS; HUMANS; MODELS, BIOLOGICAL; PHARMACEUTICAL PREPARATIONS; TISSUE DISTRIBUTION;

EID: 84896130461     PISSN: 00909556     EISSN: 1521009X     Source Type: Journal    
DOI: 10.1124/dmd.113.055558     Document Type: Short Survey

References (124)

1. Aweeka FT, Tomlanovich SJ, Prueksaritanont T, Gupta SK, and Benet LZ (1994) Pharmacokinetics of orally and intravenously administered cyclosporine in pre-kidney transplant patients. J Clin Pharmacol 34:60-67. (Pubitemid 24050367)
2. Awni WM, Kasiske BL, Heim-Duthoy K, and Rao KV (1989) Long-term cyclosporine pharmacokinetic changes in renal transplant recipients: effects of binding and metabolism. Clin Pharmacol Ther 45:41-48. (Pubitemid 19047145)
3. Back DJ, Bolt HM, Breckenridge AM, Crawford FE, Orme ML, Rowe PH, and Schindler AE (1980) The pharmacokinetics of a large (3 mg) oral dose of ethynylestradiol in women. Contraception 21:145-153. (Pubitemid 10112997)
4. Backman JT, Kyrklund C, Neuvonen M, and Neuvonen PJ (2002) Gemfibrozil greatly increases plasma concentrations of cerivastatin. Clin Pharmacol Ther 72:685-691. (Pubitemid 36021007)
5. Bansal T, Awasthi A, Jaggi M, Khar RK, and Talegaonkar S (2008) Pre-clinical evidence for altered absorption and biliary excretion of irinotecan (CPT-11) in combination with quercetin: possible contribution of P-glycoprotein. Life Sci 83:250-259.
6. Bauer S, Störmer E, Johne A, Krüger H, Budde K, Neumayer HH, Roots I, and Mai I (2003) Alterations in cyclosporin A pharmacokinetics and metabolism during treatment with St John's wort in renal transplant patients. Br J Clin Pharmacol 55:203-211. (Pubitemid 36237867)
7. Benet LZ (2010) Predicting drug disposition via application of a Biopharmaceutics Drug Disposition Classification System. Basic Clin Pharmacol Toxicol 106:162-167.
8. Bergman AJ, Burke J, Larson P, Johnson-Levonas AO, Reyderman L, Statkevich P, Maxwell SE, Kosoglou T, Murphy G, and Gottesdiener K, et al. (2006) Interaction of single-dose ezetimibe and steady-state cyclosporine in renal transplant patients. J Clin Pharmacol 46:328-336. (Pubitemid 43260320)
9. Beumer JH, Rademaker-Lakhai JM, Rosing H, Hillebrand MJ, Bosch TM, Lopez-Lazaro L, Schellens JH, and Beijnen JH (2007) Metabolism of trabectedin (ET-743, Yondelis) in patients with advanced cancer. Cancer Chemother Pharmacol 59:825-837. (Pubitemid 46440606)
10. Beumer JH, Rademaker-Lakhai JM, Rosing H, Lopez-Lazaro L, Beijnen JH, and Schellens JH (2005) Trabectedin (Yondelis, formerly ET-743), a mass balance study in patients with advanced cancer. Invest New Drugs 23:429-436. (Pubitemid 41160090)
11. Bloomer JC, Nash M, Webb A, Miller BE, Lazaar AL, Beaumont C, and Guiney WJ (2013) Assessment of potential drug interactions by characterization of human drug metabolism pathways using non-invasive bile sampling. Br J Clin Pharmacol 75:488-496.
12. Bullingham R, Monroe S, Nicholls A, and Hale M (1996) Pharmacokinetics and bioavailability of mycophenolate mofetil in healthy subjects after single-dose oral and intravenous administration. J Clin Pharmacol 36:315-324. (Pubitemid 26125953)
13. Bullingham RE, Nicholls AJ, and Kamm BR (1998) Clinical pharmacokinetics of mycophenolate mofetil. Clin Pharmacokinet 34:429-455. (Pubitemid 28273453)
14. Castellino S, Groseclose MR, Sigafoos J, Wagner D, de Serres M, Polli JW, Romach E, Myer J, and Hamilton B (2013) Central nervous system disposition and metabolism of Fosdevirine (GSK2248761), a non-nucleoside reverse transcriptase inhibitor: an LC-MS and Matrix-assisted laser desorption/ionization imaging MS investigation into central nervous system toxicity. Chem Res Toxicol 26:241-251.
15. Castellino S, Groseclose MR, and Wagner D (2011) MALDI imaging mass spectrometry: bridging biology and chemistry in drug development. Bioanalysis 3:2427-2441.
16. Chu X, Korzekwa K, Elsby R, Fenner K, Galetin A, Lai Y, Matsson P, Moss A, Nagar S, and Rosania GR, et al.; International Transporter Consortium (2013) Intracellular drug concentrations and transporters: measurement, modeling, and implications for the liver. Clin Pharmacol Ther 94:126-141.
17. Chu XY, Huskey SE, Braun MP, Sarkadi B, Evans DC, and Evers R (2004) Transport of ethinylestradiol glucuronide and ethinylestradiol sulfate by the multidrug resistance proteins MRP1, MRP2, and MRP3. J Pharmacol Exp Ther 309:156-164. (Pubitemid 38393126)
18. Chu XY, Kato Y, Niinuma K, Sudo KI, Hakusui H, and Sugiyama Y (1997) Multispecific organic anion transporter is responsible for the biliary excretion of the camptothecin derivative irinotecan and its metabolites in rats. J Pharmacol Exp Ther 281:304-314. (Pubitemid 27203082)
19. Chu XY, Kato Y, and Sugiyama Y (1999) Possible involvement of P-glycoprotein in biliary excretion of CPT-11 in rats. Drug Metab Dispos 27:440-441. (Pubitemid 29177635)
20. Chu XY, Kato Y, Ueda K, Suzuki H, Niinuma K, Tyson CA, Weizer V, Dabbs JE, Froehlich R, and Green CE, et al. (1998) Biliary excretion mechanism of CPT-11 and its metabolites in humans: involvement of primary active transporters. Cancer Res 58:5137-5143. (Pubitemid 28521174)
21. de Forni M, Bugat R, Chabot GG, Culine S, Extra JM, Gouyette A, Madelaine I, Marty ME, and Mathieu-Boue A (1994) Phase I and pharmacokinetic study of the camptothecin derivative irinotecan, administered on a weekly schedule in cancer patients. Cancer Res 54:4347-4354. (Pubitemid 24273146)
22. De Gregori S, De Gregori M, Ranzani GN, Allegri M, Minella C, and Regazzi M (2012) Morphine metabolism, transport and brain disposition. Metab Brain Dis 27:1-5.
23. de Jong FA, Scott-Horton TJ, Kroetz DL, McLeod HL, Friberg LE, Mathijssen RH, Verweij J, Marsh S, and Sparreboom A (2007) Irinotecan-induced diarrhea: functional significance of the polymorphic ABCC2 transporter protein. Clin Pharmacol Ther 81:42-49. (Pubitemid 46050866)
24. Deng Y, Madatian A, Wire MB, Bowen C, Park JW, Williams D, Peng B, Schubert E, Gorycki F, and Levy M, et al. (2011) Metabolism and disposition of eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist, in healthy human subjects. Drug Metab Dispos 39:1734-1746.
25. de Waart DR, Vlaming ML, Kunne C, Schinkel AH, and Oude Elferink RP (2009) Complex pharmacokinetic behavior of ezetimibe depends on abcc2, abcc3, and abcg2. Drug Metab Dispos 37:1698-1702.
26. Enokizono J, Kusuhara H, and Sugiyama Y (2007a) Involvement of breast cancer resistance protein (BCRP/ABCG2) in the biliary excretion and intestinal efflux of troglitazone sulfate, the major metabolite of troglitazone with a cholestatic effect. Drug Metab Dispos 35:209-214. (Pubitemid 46148731)
27. Enokizono J, Kusuhara H, and Sugiyama Y (2007b) Regional expression and activity of breast cancer resistance protein (Bcrp/Abcg2) in mouse intestine: overlapping distribution with sulfotransferases. Drug Metab Dispos 35:922-928. (Pubitemid 46798603)
28. Fahrmayr C, König J, Auge D, Mieth M, and Fromm MF (2012) Identification of drugs and drug metabolites as substrates of multidrug resistance protein 2 (MRP2) using triple-transfected MDCK-OATP1B1-UGT1A1-MRP2 cells. Br J Pharmacol 165:1836-1847.
29. Fan J, Chen S, Chow EC, and Pang KS (2010) PBPK modeling of intestinal and liver enzymes and transporters in drug absorption and sequential metabolism. Curr Drug Metab 11:743-761.
30. Funk C, Ponelle C, Scheuermann G, and Pantze M (2001) Cholestatic potential of troglitazone as a possible factor contributing to troglitazone-induced hepatotoxicity: in vivo and in vitro interaction at the canalicular bile salt export pump (Bsep) in the rat. Mol Pharmacol 59:627-635. (Pubitemid 32179943)
31. Galetin A, Gertz M, and Houston JB (2008) Potential role of intestinal first-pass metabolism in the prediction of drug-drug interactions. Expert Opin Drug Metab Toxicol 4:909-922.
32. Garcia-Calvo M, Lisnock J, Bull HG, Hawes BE, Burnett DA, Braun MP, Crona JH, Davis HR, Jr, Dean DC, and Detmers PA, et al. (2005) The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1). Proc Natl Acad Sci USA 102:8132-8137. (Pubitemid 40800055)
33. Gertz M, Cartwright CM, Hobbs MJ, Kenworthy KE, Rowland M, Houston JB, and Galetin A (2013) Cyclosporine inhibition of hepatic and intestinal CYP3A4, uptake and efflux transporters: application of PBPK modeling in the assessment of drug-drug interaction potential. Pharm Res 30:761-780.
34. Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, Chu X, Dahlin A, Evers R, Fischer V, and Hillgren KM, et al.; International Transporter Consortium (2010) Membrane transporters in drug development. Nat Rev Drug Discov 9:215-236.
35. Gill KL, Houston JB, and Galetin A (2012) Characterization of in vitro glucuronidation clearance of a range of drugs in human kidney microsomes: comparison with liver and intestinal glucuronidation and impact of albumin. Drug Metab Dispos 40:825-835.
36. Guiney WJ, Beaumont C, Thomas SR, Robertson DC, McHugh SM, Koch A, and Richards D (2011) Use of Entero-Test, a simple approach for non-invasive clinical evaluation of the biliary disposition of drugs. Br J Clin Pharmacol 72:133-142.
37. Gupta E, Lestingi TM, Mick R, Ramirez J, Vokes EE, and Ratain MJ (1994) Metabolic fate of irinotecan in humans: correlation of glucuronidation with diarrhea. Cancer Res 54:3723-3725. (Pubitemid 24241187)
38. Han JY, Lim HS, Shin ES, Yoo YK, Park YH, Lee JE, Kim HT, and Lee JS (2008) Influence of the organic anion-transporting polypeptide 1B1 (OATP1B1) polymorphisms on irinotecanpharmacokinetics and clinical outcome of patients with advanced non-small cell lung cancer. Lung Cancer 59:69-75.
39. Han YH, Busler D, Hong Y, Tian Y, Chen C, and Rodrigues AD (2010a) Transporter studies with the 3-O-sulfate conjugate of 17alpha-ethinylestradiol: assessment of human kidney drug transporters. Drug Metab Dispos 38:1064-1071.
40. Han YH, Busler D, Hong Y, Tian Y, Chen C, and Rodrigues AD (2010b) Transporter studies with the 3-O-sulfate conjugate of 17alpha-ethinylestradiol: assessment of human liver drug transporters. Drug Metab Dispos 38:1072-1082.
41. Hinton LK, Galetin A, and Houston JB (2008) Multiple inhibition mechanisms and prediction of drug-drug interactions: status of metabolism and transporter models as exemplified by gemfibrozil-drug interactions. Pharm Res 25:1063-1074. (Pubitemid 351521103)
42. Hirouchi M, Kusuhara H, Onuki R, Ogilvie BW, Parkinson A, and Sugiyama Y (2009) Construction of triple-transfected cells [organic anion-transporting polypeptide (OATP) 1B1/multidrug resistance-associated protein (MRP) 2/MRP3 and OATP1B1/MRP2/MRP4] for analysis of the sinusoidal function of MRP3 and MRP4. Drug Metab Dispos 37:2103-2111.
43. Horikawa M, Kato Y, and Sugiyama Y (2002a) Reduced gastrointestinal toxicity following inhibition of the biliary excretion of irinotecan and its metabolites by probenecid in rats. Pharm Res 19:1345-1353.
44. Horikawa M, Kato Y, Tyson CA, and Sugiyama Y (2002b) The potential for an interaction between MRP2 (ABCC2) and various therapeutic agents: probenecid as a candidate inhibitor of the biliary excretion of irinotecan metabolites. Drug Metab Pharmacokinet 17:23-33.
45. Hsu V, de L T Vieira M, Zhao P, Zhang L, Zheng JH, Nordmark A, Berglund EG, Giacomini KM, and Huang SM (2013) Towards quantitation of the effects of renal impairment and probenecid inhibition on kidney uptake and efflux transporters, using physiologically based pharmacokinetic modelling and simulations. Clin Pharmacokinet [published ahead of print].
46. Iusuf D, van de Steeg E, and Schinkel AH (2012) Hepatocyte hopping of OATP1B substrates contributes to efficient hepatic detoxification. Clin Pharmacol Ther 92:559-562.
47. Kassahun K, Pearson PG, Tang W, McIntosh I, Leung K, Elmore C, Dean D, Wang R, Doss G, and Baillie TA (2001) Studies on the metabolism of troglitazone to reactive intermediates in vitro and in vivo. Evidence for novel biotransformation pathways involving quinone methide formation and thiazolidinedione ring scission. Chem Res Toxicol 14:62-70. (Pubitemid 32064376)
48. Kharasch ED, Hoffer C, Whittington D, and Sheffels P (2003) Role of P-glycoprotein in the intestinal absorption and clinical effects of morphine. Clin Pharmacol Ther 74:543-554. (Pubitemid 37521998)
49. Kim MS, Liu DQ, Strauss JR, Capodanno I, Yao Z, Fenyk-Melody JE, Franklin RB, and Vincent SH (2003) Metabolism and disposition of gemfibrozil in Wistar and multidrug resistance-associated protein 2-deficient TR- rats. Xenobiotica 33:1027-1042. (Pubitemid 37346685)
50. Knights KM, Rowland A, and Miners JO (2013) Renal drug metabolism in humans: The potential for drug-endobiotic interactions involving cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT). Br J Clin Pharmacol 76:587-602.
51. Kobayashi M, Saitoh H, Kobayashi M, Tadano K, Takahashi Y, and Hirano T (2004) Cyclosporin A, but not tacrolimus, inhibits the biliary excretion of mycophenolic acid glucuronide possibly mediated by multidrug resistance-associated protein 2 in rats. J Pharmacol Exp Ther 309:1029-1035. (Pubitemid 38669688)
52. Koshman SL, Lalonde LD, Burton I, Tymchak WJ, and Pearson GJ (2005) Supratherapeutic response to ezetimibe administered with cyclosporine. Ann Pharmacother 39:1561-1565. (Pubitemid 41197143)
53. Kosoglou T, Statkevich P, Johnson-Levonas AO, Paolini JF, Bergman AJ, and Alton KB (2005) Ezetimibe: a review of its metabolism, pharmacokinetics and drug interactions. Clin Pharmacokinet 44:467-494. (Pubitemid 40733733)
54. Kostrubsky VE, Vore M, Kindt E, Burliegh J, Rogers K, Peter G, Altrogge D, and Sinz MW (2001) The effect of troglitazone biliary excretion on metabolite distribution and cholestasis in transporter-deficient rats. Drug Metab Dispos 29:1561-1566. (Pubitemid 33111589)
55. Kweekel D, Guchelaar HJ, and Gelderblom H (2008) Clinical and pharmacogenetic factors associated with irinotecan toxicity. Cancer Treat Rev 34:656-669.
56. Laurenty AP, Thomas F, Chatelut E, Bétrian S, Le Guellec C, Hennebelle I, Le Guellec S, and Chevreau C (2013) Irreversible hepatotoxicity after administration of trabectedin to a pleiomorphic sarcoma patient with a rare ABCC2 polymorphism: a case report. Pharmacogenomics 14:1389-1396.
57. Lee JK, Marion TL, Abe K, Lim C, Pollock GM, and Brouwer KL (2010a) Hepatobiliary disposition of troglitazone and metabolites in rat and human sandwich-cultured hepatocytes: use of Monte Carlo simulations to assess the impact of changes in biliary excretion on troglitazone sulfate accumulation. J Pharmacol Exp Ther 332:26-34.
58. Lee JK, Paine MF, and Brouwer KL (2010b) Sulindac and its metabolites inhibit multiple transport proteins in rat and human hepatocytes. J Pharmacol Exp Ther 334:410-418.
59. Li Y, Zhou J, Ramsden D, Taub ME, O'Brien D, Xu J, Busacca CA, Gonnella N, and Tweedie DJ (2013) Enzyme-transporter Interplay in the Formation and Clearance of Abundant Metabolites of Faldaprevir Found in Excreta but not in Circulation. Drug Metab Dispos 42:384-393.
60. Lloberas N, Torras J, Cruzado JM, Andreu F, Oppenheimer F, Sánchez-Plumed J, Gentil MA, Brunet M, Ekberg H, and Grinyó JM; Spanish Pharmacogenetic Symphony Substudy Group (2011) Influence of MRP2 on MPA pharmacokinetics in renal transplant recipients-results of the Pharmacogenomic Substudy within the Symphony Study. Nephrol Dial Transplant 26:3784-3793.
61. Lohr JW, Willsky GR, and Acara MA (1998) Renal drug metabolism. Pharmacol Rev 50:107-141. (Pubitemid 28158844)
62. Loi CM, Alvey CW, Randinitis EJ, Abel R, Young MA, and Koup JR (1997) Meta-analysis of steady-state pharmacokinetics of troglitazone and its metabolites. J Clin Pharmacol 37:1038-1047. (Pubitemid 27524564)
63. Loi CM, Smith DA, and Dalvie D (2013) Which metabolites circulate? Drug Metab Dispos 41:933-951.
64. Maeng HJ, Chapy H, Zaman S, and Pang KS (2012) Effects of 1α,25-dihydroxyvitamin D3 on transport and metabolism of adefovir dipivoxil and its metabolites in Caco-2 cells. Eur J Pharm Sci 46:149-166.
65. Masubuchi Y (2006) Metabolic and non-metabolic factors determining troglitazone hepatotoxicity: a review. Drug Metab Pharmacokinet 21:347-356.
66. Ménochet K, Kenworthy KE, Houston JB, and Galetin A (2012a) Simultaneous assessment of uptake and metabolism in rat hepatocytes: a comprehensive mechanistic model. J Pharmacol Exp Ther 341:2-15.
67. Ménochet K, Kenworthy KE, Houston JB, and Galetin A (2012b) Use of mechanistic modeling to assess interindividual variability and interspecies differences in active uptake in human and rat hepatocytes. Drug Metab Dispos 40:1744-1756.
68. Miners JO, Mackenzie PI, and Knights KM (2010) The prediction of drug-glucuronidation parameters in humans: UDP-glucuronosyltransferase enzyme-selective substrate and inhibitor probes for reaction phenotyping and in vitro-in vivo extrapolation of drug clearance and drug-drug interaction potential. Drug Metab Rev 42:196-208.
69. Nakagomi-Hagihara R, Nakai D, and Tokui T (2007) Inhibition of human organic anion transporter 3 mediated pravastatin transport by gemfibrozil and the metabolites in humans. Xenobiotica 37:416-426. (Pubitemid 46572887)
70. Nakatomi K, Yoshikawa M, Oka M, Ikegami Y, Hayasaka S, Sano K, Shiozawa K, Kawabata S, Soda H, and Ishikawa T, et al. (2001) Transport of 7-ethyl-10-hydroxycamptothecin (SN-38) by breast cancer resistance protein ABCG2 in human lung cancer cells. Biochem Biophys Res Commun 288:827-832. (Pubitemid 33140956)
71. Niemi M, Backman JT, Neuvonen M, and Neuvonen PJ (2003) Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: potentially hazardous interaction between gemfibrozil and repaglinide. Diabetologia 46:347-351. (Pubitemid 36547589)
72. Nozawa T, Minami H, Sugiura S, Tsuji A, and Tamai I (2005) Role of organic anion transporter OATP1B1 (OATP-C) in hepatic uptake of irinotecan and its active metabolite, 7-ethyl-10-hydroxycamptothecin: in vitro evidence and effect of single nucleotide polymorphisms. Drug Metab Dispos 33:434-439. (Pubitemid 40279945)
73. Nozawa T, Sugiura S, Nakajima M, Goto A, Yokoi T, Nezu J, Tsuji A, and Tamai I (2004) Involvement of organic anion transporting polypeptides in the transport of troglitazone sulfate: implications for understanding troglitazone hepatotoxicity. Drug Metab Dispos 32:291-294. (Pubitemid 38263886)
74. Ogilvie BW, Zhang D, Li W, Rodrigues AD, Gipson AE, Holsapple J, Toren P, and Parkinson A (2006) Glucuronidation converts gemfibrozil to a potent, metabolism-dependent inhibitor of CYP2C8: implications for drug-drug interactions. Drug Metab Dispos 34:191-197. (Pubitemid 43042661)
75. Oswald S, Giessmann T, Luetjohann D, Wegner D, Rosskopf D, Weitschies W, and Siegmund W (2006a) Disposition and sterol-lowering effect of ezetimibe are influenced by single-dose coadministration of rifampin, an inhibitor of multidrug transport proteins. Clin Pharmacol Ther 80:477-485. (Pubitemid 44767877)
76. Oswald S, Haenisch S, Fricke C, Sudhop T, Remmler C, Giessmann T, Jedlitschky G, Adam U, Dazert E, and Warzok R, et al. (2006b) Intestinal expression of P-glycoprotein (ABCB1), multidrug resistance associated protein 2 (ABCC2), and uridine diphosphate-glucuronosyltransferase 1A1 predicts the disposition and modulates the effects of the cholesterol absorption inhibitor ezetimibe in humans. Clin Pharmacol Ther 79:206-217.
77. Oswald S, König J, Lütjohann D, Giessmann T, Kroemer HK, Rimmbach C, Rosskopf D, Fromm MF, and Siegmund W (2008) Disposition of ezetimibe is influenced by polymorphisms of the hepatic uptake carrier OATP1B1. Pharmacogenet Genomics 18:559-568.
78. Oswald S, May K, Rosin J, Lütjohann D, and Siegmund W (2010a) Synergistic influence of Abcb1 and Abcc2 on disposition and sterol lowering effects of ezetimibe in rats. J Pharm Sci 99:422-429.
79. Oswald S, Meyer zu Schwabedissen HE, Nassif A, Modess C, Desta Z, Ogburn ET, Mostertz J, Keiser M, Jia J, and Hubeny A, et al. (2012) Impact of efavirenz on intestinal metabolism and transport: insights from an interaction study with ezetimibe in healthy volunteers. Clin Pharmacol Ther 91:506-513.
80. Oswald S, Nassif A, Modess C, Keiser M, Hanke U, Engel A, Lütjohann D, Weitschies W, and Siegmund W (2010b) Pharmacokinetic and pharmacodynamic interactions between the immunosuppressant sirolimus and the lipid-lowering drug ezetimibe in healthy volunteers. Clin Pharmacol Ther 87:663-667.
81. Oswald S, Nassif A, Modess C, Keiser M, Ulrich A, Runge D, Hanke U, Lütjohann D, Engel A, and Weitschies W, et al. (2011) Drug interactions between the immunosuppressant tacrolimus and the cholesterol absorption inhibitor ezetimibe in healthy volunteers. Clin Pharmacol Ther 89:524-528.
82. Oswald S, Westrup S, Grube M, Kroemer HK, Weitschies W, and Siegmund W (2006c) Disposition and sterol-lowering effect of ezetimibe in multidrug resistance-associated protein 2-deficient rats. J Pharmacol Exp Ther 318 :1293-1299. (Pubitemid 44268338)
83. Paine MF, Hart HL, Ludington SS, Haining RL, Rettie AE, and Zeldin DC (2006) The human intestinal cytochrome P450 "pie". Drug Metab Dispos 34:880-886.
84. Pang KS, Morris ME, and Sun H (2008) Formed and preformed metabolites: facts and comparisons. J Pharm Pharmacol 60:1247-1275.
85. Patel CG, Ogasawara K, and Akhlaghi F (2013) Mycophenolic acid glucuronide is transported by multidrug resistance-associated protein 2 and this transport is not inhibited by cyclosporine, tacrolimus or sirolimus. Xenobiotica 43:229-235.
86. Picard N (2013) The pharmacokinetic interaction between mycophenolic acid and cyclosporine revisited: a commentary on " Mycophenolic acid glucuronide is transported by multidrug resistance-associated protein 2 and this transport is not inhibited by cyclosporine, tacrolimus or sirolimus". Xenobiotica 43:836-838.
87. Picard N, Yee SW, Woillard JB, Lebranchu Y, Le Meur Y, Giacomini KM, and Marquet P (2010) The role of organic anion-transporting polypeptides and their common genetic variants in mycophenolic acid pharmacokinetics. Clin Pharmacol Ther 87:100-108.
88. Polli JW, Humphreys JE, Harmon KA, Webster LO, Reese MJ, and MacLauchlin CC (2012) Assessment of Remogliflozin Etabonate, a Sodium-Dependent Glucose Co-Transporter-2 Inhibitor, as a Perpetrator of Clinical Drug Interactions: A Study on Drug Transporters and Metabolic Enzymes. J Diabetes Metab 3:1-8.
89. Pou L, Brunet M, Cantarell C, Vidal E, Oppenheimer F, Monforte V, Vilardell J, Roman A, Martorell J, and Capdevila L (2001) Mycophenolic acid plasma concentrations: influence of comedication. Ther Drug Monit 23:35-38. (Pubitemid 32105962)
90. Prideaux B and Stoeckli M (2012) Mass spectrometry imaging for drug distribution studies. J Proteomics 75:4999-5013.
91. Reyes M and Benet LZ (2011) Effects of uremic toxins on transport and metabolism of different biopharmaceutics drug disposition classification system xenobiotics. J Pharm Sci 100:3831-3842.
92. Rowland A, Miners JO, and Mackenzie PI (2013) The UDP- glucuronosyltransferases: their role in drug metabolism and detoxification. Int J Biochem Cell Biol 45:1121-1132.
93. Rowland Yeo K, Aarabi M, Jamei M, and Rostami-Hodjegan A (2011) Modeling and predicting drug pharmacokinetics in patients with renal impairment. Expert Rev Clin Pharmacol 4:261-274.
94. Sabordo L, Sallustio BC, Evans AM, and Nation RL (1999) Hepatic disposition of the acyl glucuronide1-O-gemfibrozil-beta-D-glucuronide: effects of dibromosulfophthalein on membrane transport and aglycone formation. J Pharmacol Exp Ther 288:414-420. (Pubitemid 29119646)
95. Shitara Y, Hirano M, Sato H, and Sugiyama Y (2004) Gemfibrozil and its glucuronide inhibit the organic anion transporting polypeptide 2 (OATP2/OATP1B1:SLC21A6)-mediated hepatic uptake and CYP2C8-mediated metabolism of cerivastatin: analysis of the mechanism of the clinically relevant drug-drug interaction between cerivastatin and gemfibrozil. J Pharmacol Exp Ther 311:228-236. (Pubitemid 39287802)
96. Sigafoos JF, Bowers GD, Castellino S, Culp AG, Wagner DS, Reese MJ, Humphreys JE, Hussey EK, O'Connor Semmes RL, and Kapur A, et al. (2012) Assessment of the drug interaction risk for remogliflozin etabonate, a sodium-dependent glucose cotransporter-2 inhibitor: evidence from in vitro, human mass balance, and ketoconazole interaction studies. Drug Metab Dispos 40:2090-2101.
97. Skarke C, Langer M, Jarrar M, Schmidt H, Geisslinger G, and Lötsch J (2004) Probenecid interacts with the pharmacokinetics of morphine-6-glucuronide in humans. Anesthesiology 101:1394-1399. (Pubitemid 39564996)
98. Smith DA and Dalvie D (2012) Why do metabolites circulate? Xenobiotica 42:107-126.
99. Smith NF, Figg WD, and Sparreboom A (2006) Pharmacogenetics of irinotecan metabolism and transport: an update. Toxicol In Vitro 20:163-175. (Pubitemid 43087700)
100. Suchy D, Łabuzek K, Stadnicki A, and Okopień B (2011) Ezetimibe - a new approach in hypercholesterolemia management. Pharmacol Rep 63:1335-1348.
101. Sun H, Zeng YY, and Pang KS (2010) Interplay of phase II enzymes and transporters in futile cycling: influence of multidrug resistance-associated protein 2-mediated excretion of estradiol 17beta-D-glucuronide and its 3-sulfate metabolite on net sulfation in perfused TR(-) and Wistar rat liver preparations. Drug Metab Dispos 38:769-780.
102. Sun H, Zhang L, Chow EC, Lin G, Zuo Z, and Pang KS (2008) A catenary model to study transport and conjugation of baicalein, a bioactive flavonoid, in the Caco-2 cell monolayer: demonstration of substrate inhibition. J Pharmacol Exp Ther 326:117-126. (Pubitemid 351872137)
103. Takane H, Kawamoto K, Sasaki T, Moriki K, Moriki K, Kitano H, Higuchi S, Otsubo K, and Ieiri I (2009) Life-threatening toxicities in a patient with UGT1A1*6/*28 and SLCO1B1*15/*15 genotypes after irinotecan-based chemotherapy. Cancer Chemother Pharmacol 63:1165-1169.
104. Tornio A, Niemi M, Neuvonen M, Laitila J, Kalliokoski A, Neuvonen PJ, and Backman JT (2008) The effect of gemfibrozil on repaglinide pharmacokinetics persists for at least 12 h after the dose: evidence for mechanism-based inhibition of CYP2C8 in vivo. Clin Pharmacol Ther 84:403-411.
105. Uwai Y, Motohashi H, Tsuji Y, Ueo H, Katsura T, and Inui K (2007) Interaction and transport characteristics of mycophenolic acid and its glucuronide via human organic anion transporters hOAT1 and hOAT3. Biochem Pharmacol 74:161-168. (Pubitemid 46802493)
106. VandenBrink BM, Foti RS, Rock DA, Wienkers LC, and Wahlstrom JL (2011) Evaluation of CYP2C8 inhibition in vitro: utility of montelukast as a selective CYP2C8 probe substrate. Drug Metab Dispos 39:1546-1554.
107. van de Wetering K, Burkon A, Feddema W, Bot A, de Jonge H, Somoza V, and Borst P (2009) Intestinal breast cancer resistance protein (BCRP)/Bcrp1 and multidrug resistance protein 3 (MRP3)/Mrp3 are involved in the pharmacokinetics of resveratrol. Mol Pharmacol 75:876-885.
108. van de Wetering K, Zelcer N, Kuil A, Feddema W, Hillebrand M, Vlaming ML, Schinkel AH, Beijnen JH, and Borst P (2007) Multidrug resistance proteins 2 and 3 provide alternative routes for hepatic excretion of morphine-glucuronides. Mol Pharmacol 72:387-394. (Pubitemid 47124119)
109. van Heek M, Farley C, Compton DS, Hoos L, Alton KB, Sybertz EJ, and Davis HR, Jr (2000) Comparison of the activity and disposition of the novel cholesterol absorption inhibitor, SCH58235, and its glucuronide, SCH60663. Br J Pharmacol 129:1748-1754. (Pubitemid 30219019)
110. van Waterschoot RA, Eman RM, Wagenaar E, van der Kruijssen CM, Rosing H, Beijnen JH, and Schinkel AH (2009) ABCC2, ABCC3, and ABCB1, but not CYP3A, Protect against Trabectedin-Mediated Hepatotoxicity. Clin Cancer Res 15:7616-7623.
111. Varma MV, Lai Y, Kimoto E, Goosen TC, El-Kattan AF, and Kumar V (2013) Mechanistic modeling to predict the transporter- and enzyme-mediated drug-drug interactions of repaglinide. Pharm Res 30:1188-1199.
112. Wang CP, Burckart GJ, Ptachcinski RJ, Venkataramanan R, Schwinghammer T, Hakala T, Griffith B, Hardesty R, Shadduck R, and Knapp J, et al. (1988) Cyclosporine metabolite concentrations in the blood of liver, heart, kidney, and bone marrow transplant patients. Transplant Proc 20(2, Suppl 2)591-596.
113. Yeung CK, Fujioka Y, Hachad H, Levy RH, and Isoherranen N (2011) Are circulating metabolites important in drug-drug interactions?: Quantitative analysis of risk prediction and inhibitory potency. Clin Pharmacol Ther 89:105-113.
114. Zamek-Gliszczynski MJ, Abraham TL, Alberts JJ, Kulanthaivel P, Jackson KA, Chow KH, McCann DJ, Hu H, Anderson S, and Furr NA, et al. (2013a) Pharmacokinetics, metabolism, and excretion of the glycogen synthase kinase-3 inhibitor LY2090314 in rats, dogs, and humans: a case study in rapid clearance by extensive metabolism with low circulating metabolite exposure. Drug Metab Dispos 41:714-726.
115. Zamek-Gliszczynski MJ, Day JS, Hillgren KM, and Phillips DL (2011) Efflux transport is an important determinant of ethinylestradiol glucuronide and ethinylestradiol sulfate pharmacokinetics. Drug Metab Dispos 39:1794-1800.
116. Zamek-Gliszczynski MJ, Hoffmaster KA, Nezasa K, Tallman MN, and Brouwer KL (2006a) Integration of hepatic drug transporters and phase II metabolizing enzymes: mechanisms of hepatic excretion of sulfate, glucuronide, and glutathione metabolites. Eur J Pharm Sci 27:447-486. (Pubitemid 43363339)
117. Zamek-Gliszczynski MJ, Hoffmaster KA, Tweedie DJ, Giacomini KM, and Hillgren KM (2012) Highlights from the International Transporter Consortium second workshop. Clin Pharmacol Ther 92:553-556.
118. Zamek-Gliszczynski MJ, Kalvass JC, Pollack GM, and Brouwer KL (2009) Relationship between drug/metabolite exposure and impairment of excretory transport function. Drug Metab Dispos 37:386-390.
119. Zamek-Gliszczynski MJ, Lee CA, Poirier A, Bentz J, Chu X, Ellens H, Ishikawa T, Jamei M, Kalvass JC, and Nagar S, et al.; International Transporter Consortium (2013b) ITC recommendations for transporter kinetic parameter estimation and translational modeling of transport-mediated PK and DDIs in humans. Clin Pharmacol Ther 94:64-79.
120. Zamek-Gliszczynski MJ, Nezasa K, Tian X, Bridges AS, Lee K, Belinsky MG, Kruh GD, and Brouwer KL (2006b) Evaluation of the role of multidrug resistance-associated protein (Mrp) 3 and Mrp4 in hepatic basolateral excretion of sulfate and glucuronide metabolites of acetaminophen, 4-methylumbelliferone, and harmol in Abcc3-/- and Abcc4-/- mice. J Pharmacol Exp Ther 319:1485-1491.
121. Zelcer N, van de Wetering K, Hillebrand M, Sarton E, Kuil A, Wielinga PR, Tephly T, Dahan A, Beijnen JH, and Borst P (2005) Mice lacking multidrug resistance protein 3 show altered morphine pharmacokinetics and morphine-6-glucuronide antinociception. Proc Natl Acad Sci USA 102:7274-7279. (Pubitemid 40696369)
122. Zhang H, Cui D, Wang B, Han YH, Balimane P, Yang Z, Sinz M, and Rodrigues AD (2007) Pharmacokinetic drug interactions involving 17alpha-ethinylestradiol: a new look at an old drug. Clin Pharmacokinet 46:133-157. (Pubitemid 46193058)
123. Zhao P, Vieira MdeL, Grillo JA, Song P, Wu TC, Zheng JH, Arya V, Berglund
124. Zimmerman EI, Hu S, Roberts JL, Gibson AA, Orwick SJ, Li L, Sparreboom A, and Baker SD (2013) Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide. Clin Cancer Res 19:1458-1466.