Role of gemfibrozil as an inhibitor of CYP2C8 and membrane transporters

Expert Opinion on Drug Metabolism and Toxicology

Volumn 13, Issue 1, 2017, Pages 83-95

  Tornio, Aleksi ^a   Neuvonen, Pertti J ^a   Niemi, Mikko ^a   Backman, Janne T ^a  

^a HELSINKI UNIVERSITY CENTRAL HOSPITAL   (Finland)

Author keywords

CYP2C8; drug drug interaction; gemfibrozil; mechanism based inhibition; OAT3; OATP1B1

Indexed keywords

ACID; ANTILIPEMIC AGENT; ATORVASTATIN; CERIVASTATIN; CYTOCHROME P450 2C8; DABRAFENIB; DAPRODUSTAT; DASABUVIR; EMPAGLIFLOZIN; ENZALUTAMIDE; GEMFIBROZIL; GLIMEPIRIDE; IBUPROFEN; IMATINIB; LOPERAMIDE; MEMBRANE PROTEIN; MEVINOLIN; MONTELUKAST; PARITAPREVIR; PITAVASTATIN; REPAGLINIDE; ROSIGLITAZONE; ROSUVASTATIN; SIMVASTATIN; SITAGLIPTIN; TREPROSTINIL; CARRIER PROTEIN; CYP2C8 PROTEIN, HUMAN; CYTOCHROME P450 2C8 INHIBITOR; GEMFIBROZIL 1-O-ACYLGLUCURONIDE; GLUCURONIC ACID;

CLINICAL PHARMACOLOGY; DRUG EFFECT; DRUG MECHANISM; ENZYME INHIBITION; HUMAN; IN VITRO STUDY; MEMBRANE TRANSPORT; PROTEIN INTERACTION; REVIEW; ANALOGS AND DERIVATIVES; DRUG EFFECTS; DRUG INTERACTION; METABOLISM;

CYTOCHROME P-450 CYP2C8; CYTOCHROME P-450 CYP2C8 INHIBITORS; DRUG INTERACTIONS; GEMFIBROZIL; GLUCURONATES; HUMANS; HYPOLIPIDEMIC AGENTS; MEMBRANE TRANSPORT PROTEINS;

EID: 85003604007     PISSN: 17425255     EISSN: 17447607     Source Type: Journal    
DOI: 10.1080/17425255.2016.1227791     Document Type: Review

References (110)

1. Smith TC., Toleration and bioavailability of gemfibrozil in healthy men. Proc R Soc Med. 1976;69(Suppl 2):24–27.
2. Todd PA, Ward A. Gemfibrozil. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in dyslipidaemia. Drugs. 1988;36:314–339.
3. Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study:primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med. 1987;317:1237–1245.
4. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med. 1999;341:410–418.
5. Miller DB, Spence JD. Clinical pharmacokinetics of fibric acid derivatives (fibrates). Clin Pharmacokinet. 1998;34:155–162.
6. Backman JT, Kyrklund C, Kivistö KT, et al. Plasma concentrations of active simvastatin acid are increased by gemfibrozil. Clin Pharmacol Ther. 2000;68:122–129.• Clinical drug interaction study reporting that gemfibrozil increases the plasma concentrations of simvastatin acid, and suggesting a role for pharmacokinetic mechanisms in gemfibrozil–statin interactions.
7. Backman JT, Kyrklund C, Neuvonen M, et al. Gemfibrozil greatly increases plasma concentrations of cerivastatin. Clin Pharmacol Ther. 2002;72:685–691.••The original drug interaction study reporting the effect of gemfibrozil on the pharmacokinetics of cerivastatin, and demonstrating the strong CYP2C8 inhibitory effect of gemfibrozil.
8. Backman JT, Luurila H, Neuvonen M, et al. Rifampin markedly decreases and gemfibrozil increases the plasma concentrations of atorvastatin and its metabolites. Clin Pharmacol Ther. 2005;78:154–167.
9. Kyrklund C, Backman JT, Kivistö KT, et al. Plasma concentrations of active lovastatin acid are markedly increased by gemfibrozil but not by bezafibrate. Clin Pharmacol Ther. 2001;69:340–345.
10. Kyrklund C, Backman JT, Neuvonen M, et al. Gemfibrozil increases plasma pravastatin concentrations and reduces pravastatin renal clearance. Clin Pharmacol Ther. 2003;73:538–544.
11. Schneck DW, Birmingham BK, Zalikowski JA, et al. The effect of gemfibrozil on the pharmacokinetics of rosuvastatin. Clin Pharmacol Ther. 2004;75:455–463.
12. Whitfield LR, Porcari AR, Alvey C, et al. Effect of gemfibrozil and fenofibrate on the pharmacokinetics of atorvastatin. J Clin Pharmacol. 2011;51:378–388.
13. Mathew P, Cuddy T, Tracewell WG, et al. An open-label study on the pharmacokinetics (PK) of pitavastatin (NK-104) when administered concomitantly with fenofibrate or gemfibrozil in healthy volunteers. Clin Pharmacol Ther. 2004;75:P33.
14. Furberg CD, Pitt B. Withdrawal of cerivastatin from the world market. Curr Control Trials Cardiovasc Med. 2001;2:205–207.
15. Shitara Y, Hirano M, Sato H, et al. 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. 2004;311:228–236.••First in vitro study reporting the inhibitory effect of gemfibrozil and its glucuronide on OATP1B1, as well as the inhibitory effect of gemfibrozil glucuronide on CYP2C8.
16. Wang J-S, Neuvonen M, Wen X, et al. Gemfibrozil inhibits CYP2C8-mediated cerivastatin metabolism in human liver microsomes. Drug Metab Dispos. 2002;30:1352–1356.• First in vitro study reporting the inhibitory effect of gemfibrozil on CYP2C8, and that the formation of the main hydroxy metabolite of cerivastatin is predominantly mediated by CYP2C8.
17. Ogilvie BW, Zhang D, Li W, et al. Glucuronidation converts gemfibrozil to a potent, metabolism-dependent inhibitor of CYP2C8:implications for drug-drug interactions. Drug Metab Dispos. 2006;34:191–197.••The original study reporting mechanism-based inhibition of CYP2C8 by gemfibrozil 1-O-β-glucuronide in vitro.
18. Nakagomi-Hagihara R, Nakai D, Tokui T. Inhibition of human organic anion transporter 3 mediated pravastatin transport by gemfibrozil and the metabolites in humans. Xenobiotica. 2007;37:416–426.
19. Sando KR, Knight M. Nonstatin therapies for management of dyslipidemia:a review. Clin Ther. 2015;37:2153–2179.
20. Guideline on the investigation of drug interactions. European Medicines Agency. 2012 [cited 2016 Aug4]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/07/WC500129606.pdf
21. Drug development and drug interactions:table of substrates, inhibitors and inducers. Food and Drug Administration. 2014 [cited 2016 Aug4]. Available from: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm
22. Honkalammi J, Niemi M, Neuvonen PJ, et al. Gemfibrozil is a strong inactivator of CYP2C8 in very small multiple doses. Clin Pharmacol Ther. 2012;91:846–855.• A publication describing strong inhibition of CYP2C8 by small repeated doses of gemfibrozil in humans.
23. Backman JT, Filppula AM, Niemi M, et al. Role of cytochrome P450 2C8 in drug metabolism and interactions. Pharmacol Rev. 2016;68:168–241.•• A comprehensive review about CYP2C8 with special regard to pharmacogenetics, substrates, and drug interactions.
24. Backes JM, Gibson CA, Ruisinger JF, et al. Fibrates:what have we learned in the past 40 years? Pharmacotherapy. 2007;27:412–424.
25. Grundy SM, Vega GL. Fibric acids:effects on lipids and lipoprotein metabolism. Am J Med. 1987;83:9–20.
26. Neuvonen PJ, Niemi M, Backman JT. Drug interactions with lipid-lowering drugs:mechanisms and clinical relevance. Clin Pharmacol Ther. 2006;80:565–581.• A comprehensive review of drug interactions involving lipid-lowering drugs.
27. Mano Y, Usui T, Kamimura H. The UDP-glucuronosyltransferase 2B7 isozyme is responsible for gemfibrozil glucuronidation in the human liver. Drug Metab Dispos. 2007;35:2040–2044.
28. Kimoto E, Li R, Scialis RJ, et al. Hepatic disposition of gemfibrozil and its major metabolite gemfibrozil 1-O-β-glucuronide. Mol Pharm. 2015;12:3943–3952.
29. Sallustio BC, Fairchild BA, Shanahan K, et al. Disposition of gemfibrozil and gemfibrozil acyl glucuronide in the rat isolated perfused liver. Drug Metab Dispos. 1996;24:984–989.
30. Spencer CM, Barradell LB. Gemfibrozil. A reappraisal of its pharmacological properties and place in the management of dyslipidaemia. Drugs. 1996;51:982–1018.
31. Tornio A, Niemi M, Neuvonen M, et al. 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. 2008;84:403–411.•• First study in humans documenting the long-lasting inhibition of CYP2C8 by gemfibrozil.
32. Backman JT, Honkalammi J, Neuvonen M, et al. CYP2C8 activity recovers within 96 hours after gemfibrozil dosing:estimation of CYP2C8 half-life using repaglinide as an in vivo probe. Drug Metab Dispos. 2009;37:2359–2366.•• A clinical study documenting the time needed for full recovery of CYP2C8 after gemfibrozil treatment, and estimating the turnover half-life of CYP2C8.
33. Baer BR, DeLisle RK, Allen A. Benzylic oxidation of gemfibrozil-1-O-beta-glucuronide by P450 2C8 leads to heme alkylation and irreversible inhibition. Chem Res Toxicol. 2009;22:1298–1309.•• The original report describing the molecular mechanism of irreversible CYP2C8 inhibition by gemfibrozil-1-O-β-glucuronide.
34. Jenkins SM, Zvyaga T, Johnson SR, et al. Studies to further investigate the inhibition of human liver microsomal CYP2C8 by the acyl-β-glucuronide of gemfibrozil. Drug Metab Dispos. 2011;39:2421–2430.
35. Prueksaritanont T, Tang C, Qiu Y, et al. Effects of fibrates on metabolism of statins in human hepatocytes. Drug Metab Dispos. 2002;30:1280–1287.
36. Wen X, Wang JS, Backman JT, et al. Gemfibrozil is a potent inhibitor of human cytochrome P450 2C9. Drug Metab Dispos. 2001;29:1359–1361.
37. Fujino H, Shimada S, Yamada I, et al. Studies on the interaction between fibrates and statins using human hepatic microsomes. Arzneimittelforschung. 2003;53:701–707.
38. Venkatakrishnan K, Obach RS, Rostami-Hodjegan A. Mechanism-based inactivation of human cytochrome P450 enzymes:strategies for diagnosis and drug-drug interaction risk assessment. Xenobiotica. 2007;37:1225–1256.
39. Silverman RB. Mechanism-based enzyme inactivators. Methods Enzymol. 1995;249:240–283.
40. Lin JH, Lu AY. Inhibition and induction of cytochrome P450 and the clinical implications. Clin Pharmacokinet. 1998;35:361–390.
41. Gan J, Chen W, Shen H, et al. Repaglinide-gemfibrozil drug interaction:inhibition of repaglinide glucuronidation as a potential additional contributing mechanism. Br J Clin Pharmacol. 2010;70:870–880.
42. Hirano M, Maeda K, Shitara Y, et al. Drug-drug interaction between pitavastatin and various drugs via OATP1B1. Drug Metab Dispos. 2006;34:1229–1236.
43. Nakagomi-Hagihara R, Nakai D, Tokui T, et al. Gemfibrozil and its glucuronide inhibit the hepatic uptake of pravastatin mediated by OATP1B1. Xenobiotica. 2007;37:474–486.
44. Vildhede A, Karlgren M, Svedberg EK, et al. Hepatic uptake of atorvastatin:influence of variability in transporter expression on uptake clearance and drug-drug interactions. Drug Metab Dispos. 2014;42:1210–1218.
45. Yamazaki M, Li B, Louie SW, et al. Effects of fibrates on human organic anion-transporting polypeptide 1B1-, multidrug resistance protein 2- and P-glycoprotein-mediated transport. Xenobiotica. 2005;35:737–753.
46. Watanabe T, Kusuhara H, Watanabe T, et al. Prediction of the overall renal tubular secretion and hepatic clearance of anionic drugs and a renal drug-drug interaction involving organic anion transporter 3 in humans by in vitro uptake experiments. Drug Metab Dispos. 2011;39:1031–1038.
47. Ho RH, Tirona RG, Leake BF, et al. Drug and bile acid transporters in rosuvastatin hepatic uptake:function, expression, and pharmacogenetics. Gastroenterology. 2006;130:1793–1806.
48. Noé J, Portmann R, Brun M-E, et al. Substrate-dependent drug-drug interactions between gemfibrozil, fluvastatin and other organic anion-transporting peptide (OATP) substrates on OATP1B1, OATP2B1, and OATP1B3. Drug Metab Dispos. 2007;35:1308–1314.
49. Pedersen JM, Matsson P, Bergström CAS, et al. Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol Sci. 2013;136:328–343.
50. Hinton LK, Galetin A, Houston JB. Multiple inhibition mechanisms and prediction of drug-drug interactions:status of metabolism and transporter models as exemplified by gemfibrozil-drug interactions. Pharm Res. 2008;25:1063–1074.
51. Shen H, Yang Z, Mintier G, et al. Cynomolgus monkey as a potential model to assess drug interactions involving hepatic organic anion transporting polypeptides:in vitro, in vivo, and in vitro-to-in vivo extrapolation. J Pharmacol Exp Ther. 2013;344:673–685.
52. Kivistö KT, Zukunft J, Hofmann U, et al. Characterisation of cerivastatin as a P-glycoprotein substrate:studies in P-glycoprotein-expressing cell monolayers and mdr1a/b knock-out mice. Naunyn Schmiedebergs Arch Pharmacol. 2004;370:124–130.
53. Lilja JJ, Backman JT, Neuvonen PJ. Effect of gemfibrozil on the pharmacokinetics and pharmacodynamics of racemic warfarin in healthy subjects. Br J Clin Pharmacol. 2005;59:433–439.
54. Bidstrup TB, Bjørnsdottir I, Sidelmann UG, et al. CYP2C8 and CYP3A4 are the principal enzymes involved in the human in vitro biotransformation of the insulin secretagogue repaglinide. Br J Clin Pharmacol. 2003;56:305–314.
55. Kajosaari LI, Laitila J, Neuvonen PJ, et al. Metabolism of repaglinide by CYP2C8 and CYP3A4 in vitro:effect of fibrates and rifampicin. Basic Clin Pharmacol Toxicol. 2005;97:249–256.
56. Säll C, Houston JB, Galetin A. A comprehensive assessment of repaglinide metabolic pathways:impact of choice of in vitro system and relative enzyme contribution to in vitro clearance. Drug Metab Dispos. 2012;40:1279–1289.
57. Niemi M, Backman JT, Neuvonen M, et al. Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide:potentially hazardous interaction between gemfibrozil and repaglinide. Diabetologia. 2003;46:347–351.• First clinical study documenting the strong effect of gemfibrozil on the pharmacokinetics and glucose-lowering effect of repaglinide.
58. Suttle AB, Grossmann KF, Ouellet D, et al. Assessment of the drug interaction potential and single- and repeat-dose pharmacokinetics of the BRAF inhibitor dabrafenib. J Clin Pharmacol. 2015;55:392–400.
59. Johnson BM, Stier BA, Caltabiano S. Effect of food and gemfibrozil on the pharmacokinetics of the novel prolyl hydroxylase inhibitor GSK1278863. Clin Pharmacol Drug Dev. 2014;3:109–117.
60. Menon RM, Badri PS, Wang T, et al. Drug-drug interaction profile of the all-oral anti-hepatitis C virus regimen of paritaprevir/ritonavir, ombitasvir, and dasabuvir. J Hepatol. 2015;63:20–29.
61. Macha S, Koenen R, Sennewald R, et al. Effect of gemfibrozil, rifampicin, or probenecid on the pharmacokinetics of the SGLT2 inhibitor empagliflozin in healthy volunteers. Clin Ther. 2014;36:280–290.e1.
62. Gibbons JA, de Vries M, Krauwinkel W, et al. Pharmacokinetic drug interaction studies with enzalutamide. Clin Pharmacokinet. 2015;54:1057–1069.
63. Niemi M, Neuvonen PJ, Kivistö KT. Effect of gemfibrozil on the pharmacokinetics and pharmacodynamics of glimepiride. Clin Pharmacol Ther. 2001;70:439–445.
64. Tornio A, Niemi M, Neuvonen PJ, et al. Stereoselective interaction between the CYP2C8 inhibitor gemfibrozil and racemic ibuprofen. Eur J Clin Pharmacol. 2007;63:463–469.
65. Filppula AM, Tornio A, Niemi M, et al. Gemfibrozil impairs imatinib absorption and inhibits the CYP2C8-mediated formation of its main metabolite. Clin Pharmacol Ther. 2013;94:383–393.
66. Niemi M, Tornio A, Pasanen MK, et al. Itraconazole, gemfibrozil and their combination markedly raise the plasma concentrations of loperamide. Eur J Clin Pharmacol. 2006;62:463–472.
67. Karonen T, Filppula A, Laitila J, et al. Gemfibrozil markedly increases the plasma concentrations of montelukast:a previously unrecognized role for CYP2C8 in the metabolism of montelukast. Clin Pharmacol Ther. 2010;88:223–230.
68. Deng L-J, Wang F, Li H-D. Effect of gemfibrozil on the pharmacokinetics of pioglitazone. Eur J Clin Pharmacol. 2005;61:831–836.
69. Jaakkola T, Backman JT, Neuvonen M, et al. Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics of pioglitazone. Clin Pharmacol Ther. 2005;77:404–414.
70. Aquilante CL, Kosmiski LA, Bourne DWA, et al. Impact of the CYP2C8 *3 polymorphism on the drug-drug interaction between gemfibrozil and pioglitazone. Br J Clin Pharmacol. 2013;75:217–226.
71. Niemi M, Backman JT, Granfors M, et al. Gemfibrozil considerably increases the plasma concentrations of rosiglitazone. Diabetologia. 2003;46:1319–1323.
72. Arun KP, Meda VS, Kucherlapati VS, et al. Pharmacokinetic drug interaction between gemfibrozil and sitagliptin in healthy Indian male volunteers. Eur J Clin Pharmacol. 2012;68:709–714.
73. Clinical pharmacology and biopharmaceutics review(s):Tyvaso. Food and Drug Administration/Center for Drug Evaluation and Research. 2009 [cited 2016 Jan29]. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022387s000ClinPharmR.pdf
74. Kajosaari LI, Niemi M, Backman JT, et al. Telithromycin, but not montelukast, increases the plasma concentrations and effects of the cytochrome P450 3A4 and 2C8 substrate repaglinide. Clin Pharmacol Ther. 2006;79:231–242.
75. Walsky RL, Obach RS, Gaman EA, et al. Selective inhibition of human cytochrome P4502C8 by montelukast. Drug Metab Dispos. 2005;33:413–418.
76. Filppula AM, Laitila J, Neuvonen PJ, et al. Reevaluation of the microsomal metabolism of montelukast:major contribution by CYP2C8 at clinically relevant concentrations. Drug Metab Dispos. 2011;39:904–911.
77. Baldwin SJ, Clarke SE, Chenery RJ. Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of rosiglitazone. Br J Clin Pharmacol. 1999;48:424–432.
78. Jaakkola T, Laitila J, Neuvonen PJ, et al. Pioglitazone is metabolised by CYP2C8 and CYP3A4 in vitro:potential for interactions with CYP2C8 inhibitors. Basic Clin Pharmacol Toxicol. 2006;99:44–51.
79. Filppula AM, Laitila J, Neuvonen PJ, et al. Potent mechanism-based inhibition of CYP3A4 by imatinib explains its liability to interact with CYP3A4 substrates. Br J Pharmacol. 2012;165:2787–2798.
80. Filppula AM, Neuvonen M, Laitila J, et al. Autoinhibition of CYP3A4 leads to important role of CYP2C8 in imatinib metabolism:variability in CYP2C8 activity may alter plasma concentrations and response. Drug Metab Dispos. 2013;41:50–59.
81. Tornio A, Neuvonen PJ, Backman JT. The CYP2C8 inhibitor gemfibrozil does not increase the plasma concentrations of zopiclone. Eur J Clin Pharmacol. 2006;62:645–651.
82. Pasanen MK, Neuvonen M, Neuvonen PJ, et al. SLCO1B1 polymorphism markedly affects the pharmacokinetics of simvastatin acid. Pharmacogenet Genomics. 2006;16:873–879.
83. Tornio A, Vakkilainen J, Neuvonen M, et al. SLCO1B1 polymorphism markedly affects the pharmacokinetics of lovastatin acid. Pharmacogenet Genomics. 2015;25:382–387.
84. Bergman E, Matsson EM, Hedeland M, et al. Effect of a single gemfibrozil dose on the pharmacokinetics of rosuvastatin in bile and plasma in healthy volunteers. J Clin Pharmacol. 2010;50:1039–1049.
85. Spence JD, Munoz CE, Hendricks L, et al. Pharmacokinetics of the combination of fluvastatin and gemfibrozil. Am J Cardiol. 1995;76:80A–83A.
86. Niemi M. Transporter pharmacogenetics and statin toxicity. Clin Pharmacol Ther. 2010;87:130–133.
87. Niemi M, Pasanen MK, Neuvonen PJ. SLCO1B1 polymorphism and sex affect the pharmacokinetics of pravastatin but not fluvastatin. Clin Pharmacol Ther. 2006;80:356–366.
88. Niemi M, Pasanen MK, Neuvonen PJ. Organic anion transporting polypeptide 1B1:a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev. 2011;63:157–181.• A comprehensive review of organic anion transporting polypeptide 1B1.
89. Varma MV, Lin J, Bi YA, et al. Quantitative rationalization of gemfibrozil drug interactions:consideration of transporters-enzyme interplay and the role of circulating metabolite gemfibrozil 1-O-beta-glucuronide. Drug Metab Dispos. 2015;43:1108–1118.• A paper providing quantitative rationalization to gemfibrozil drug interactions using both static mechanistic and dynamic PBPK models.
90. Niemi M, Backman JT, Juntti-Patinen L, et al. Coadministration of gemfibrozil and itraconazole has only a minor effect on the pharmacokinetics of the CYP2C9 and CYP3A4 substrate nateglinide. Br J Clin Pharmacol. 2005;60:208–217.
91. Kalliokoski A, Neuvonen PJ, Niemi M. SLCO1B1 polymorphism and oral antidiabetic drugs. Basic Clin Pharmacol Toxicol. 2010;107:775–781.
92. Tornio A, Niemi M, Neuvonen PJ, et al. Drug interactions with oral antidiabetic agents:pharmacokinetic mechanisms and clinical implications. Trends Pharmacol Sci. 2012;33:312–322.• A practical review of drug interactions involving antidiabetic agents.
93. Kudo T, Hisaka A, Sugiyama Y, et al. Analysis of the repaglinide concentration increase produced by gemfibrozil and itraconazole based on the inhibition of the hepatic uptake transporter and metabolic enzymes. Drug Metab Dispos. 2013;41:362–371.
94. Yoshida K, Maeda K, Sugiyama Y. Transporter-mediated drug–drug interactions involving OATP substrates:predictions based on in vitro inhibition studies. Clin Pharmacol Ther. 2012;91:1053–1064.
95. Honkalammi J, Niemi M, Neuvonen PJ, et al. Dose-dependent interaction between gemfibrozil and repaglinide in humans:strong inhibition of CYP2C8 with subtherapeutic gemfibrozil doses. Drug Metab Dispos. 2011;39:1977–1986.
96. Varma MVS, Lai Y, Kimoto E, et al. Mechanistic modeling to predict the transporter- and enzyme-mediated drug-drug interactions of repaglinide. Pharm Res. 2013;30:1188–1199.
97. Busse KH, Hadigan C, Chairez C, et al. Gemfibrozil concentrations are significantly decreased in the presence of lopinavir-ritonavir. J Acquir Immune Defic Syndr. 2009;52:235–239.
98. Honkalammi J, Niemi M, Neuvonen PJ, et al. Mechanism-based inactivation of CYP2C8 by gemfibrozil occurs rapidly in humans. Clin Pharmacol Ther. 2011;89:579–586.
99. Ibarra-Barrueta O, Palacios-Zabalza I, Mora-Atorrasagasti O, et al. Effect of concomitant use of montelukast and efavirenz on neuropsychiatric adverse events. Ann Pharmacother. 2014;48:145–148.
100. Kazmi F, Barbara JE, Yerino P, et al. A long-standing mystery solved:the formation of 3-hydroxydesloratadine is catalyzed by CYP2C8 but prior glucuronidation of desloratadine by UDP-glucuronosyltransferase 2B10 is an obligatory requirement. Drug Metab Dispos. 2015;43:523–533.
101. Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis. N Engl J Med. 2002;346:539–540.
102. Rahman A, Korzekwa KR, Grogan J, et al. Selective biotransformation of taxol to 6 alpha-hydroxytaxol by human cytochrome P450 2C8. Cancer Res. 1994;54:5543–5546.
103. Tan AR, Dowlati A, Stein MN, et al. Phase I study of weekly paclitaxel in combination with pazopanib and lapatinib in advanced solid malignancies. Br J Cancer. 2014;110:2647–2654.
104. Tornio A, Filppula AM, Kailari O, et al. Glucuronidation converts clopidogrel to a strong time-dependent inhibitor of CYP2C8:a phase II metabolite as a perpetrator of drug-drug interactions. Clin Pharmacol Ther. 2014;96:498–507.•• An elegant study based on a combination of in vitro, in silico, and clinical methods, showing that clopidogrel is a strong inhibitor of CYP2C8 and that its acyl glucuronide metabolite is a metabolism-dependent inhibitor of CYP2C8.
105. Bergmann TK, Filppula AM, Launiainen T, et al. Neurotoxicity and low paclitaxel clearance associated with concomitant clopidogrel therapy in a 60 year old Caucasian woman with ovarian carcinoma. Br J Clin Pharmacol. 2016;81:313–315.
106. Sane RS, Ramsden D, Sabo JP, et al. Contribution of major metabolites towards complex drug-drug interactions of deleobuvir:in vitro predictions and in vivo outcomes. Drug Metab Dispos. 2015 [cited 2015 Dec18]. DOI:10.1124/dmd.115.066985
107. Floyd JS, Kaspera R, Marciante KD, et al. A screening study of drug-drug interactions in cerivastatin users:an adverse effect of clopidogrel. Clin Pharmacol Ther. 2012;91:896–904.
108. Kazmi F, Smith B, Hvenegaard MG, et al. Identification of a novel carbamoyl glucuronide as a metabolism-dependent inhibitor of CYP2C8. 9th International ISSX Meeting; 2010 Sep 4–8; Istanbul, Turkey. 2010 [cited 2016 Feb2]. Available from: https://issx.confex.com/issx/intl9/webprogram/Paper21723.html
109. Karlgren M, Ahlin G, Bergström CAS, et al. In vitro and in silico strategies to identify OATP1B1 inhibitors and predict clinical drug-drug interactions. Pharm Res. 2012;29:411–426.
110. Taxak N, Bharatam PV. 2D QSAR study for gemfibrozil glucuronide as the mechanism-based inhibitor of CYP2C8. Indian J Pharm Sci. 2013;75:680–687.