Multiple inhibition mechanisms and prediction of drug-drug interactions: Status of metabolism and transporter models as exemplified by gemfibrozil-drug interactions

Pharmaceutical Research

Volumn 25, Issue 5, 2008, Pages 1063-1074

  Hinton, Laura K ^a   Galetin, Aleksandra ^a   Houston, J Brian ^a  

^a UNIVERSITY OF MANCHESTER   (United Kingdom)

Author keywords

CYP2C8; Drug drug interactions; Enzyme inhibition; Gemfibrozil; OATP1B1

Indexed keywords

ATORVASTATIN; CERIVASTATIN; CYCLOSPORIN; CYTOCHROME P450 2C8; CYTOCHROME P450 2C9; CYTOCHROME P450 3A4; GEMFIBROZIL; GLIMEPIRIDE; LOPERAMIDE; MEVINOLIN; ORGANIC ANION TRANSPORTER 1; PIOGLITAZONE; PRAVASTATIN; REPAGLINIDE; ROSIGLITAZONE; ROSUVASTATIN; SIMVASTATIN; ZOPICLONE;

AREA UNDER THE CURVE; ARTICLE; DATA BASE; DRUG METABOLISM; DRUG PROTEIN BINDING; DRUG TRANSPORT; ENZYME ACTIVITY; ENZYME INHIBITION; HUMAN; HUMAN CELL; IC 50; KIDNEY CELL; LIVER MICROSOME; MATHEMATICAL MODEL; PREDICTION; PRIORITY JOURNAL;

ANTILIPEMIC AGENTS; AREA UNDER CURVE; ARYL HYDROCARBON HYDROXYLASES; CARRIER PROTEINS; CELL LINE; CYCLOSPORINE; DATABASES, FACTUAL; DRUG INTERACTIONS; ENZYME INHIBITORS; GEMFIBROZIL; GLUCURONIDES; HUMANS; IMMUNOSUPPRESSIVE AGENTS; KINETICS; PREDICTIVE VALUE OF TESTS;

EID: 42049097101     PISSN: 07248741     EISSN: 1573904X     Source Type: Journal    
DOI: 10.1007/s11095-007-9446-6     Document Type: Article

References (62)

1. G. T. Tucker, J. B. Houston, and S. M. Huang. Optimizing drug development: strategies to assess drug metabolism/transporter interaction potential-towards a consensus. Br. J. Clin. Pharmacol. 52(1):107-117 (2001).
2. K. Ito, H. S. Brown, and J. B. Houston. Database analyses for the prediction of in vivo drug-drug interactions from in vitro data. Br. J. Clin. Pharmacol. 57(4):473-486 (2004).
3. A. Rostami-Hodjegan and G. Tucker. 'In silico' simulations to assess the 'in vivo' consequences of 'in vitro' metabolic drug-drug interactions. Drug Discov. Today 1(4):441-448 (2004).
4. Y. H. Wang, D. R. Jones, and S. D. Hall. Prediction of cytochrome P450 3A inhibition by verapamil enantiomers and their metabolites. Drug Metab. Dispos. 32(2):259-266 (2004).
5. H. S. Brown, K. Ito, A. Galetin, and J. B. Houston. Prediction of in vivo drug-drug interactions from in vitro data: impact of incorporating parallel pathways of drug elimination and inhibitor absorption rate constant. Br. J. Clin. Pharmacol. 60(5):508-518 (2005).
6. A. Galetin, K. Ito, D. Hallifax, and J. B. Houston. CYP3A4 substrate selection and substitution in the prediction of potential drug-drug interactions. J. Pharmacol. Exp. Ther. 314(1):180-190 (2005).
7. K. Ito, D. Hallifax, R. S. Obach, and J. B. Houston. Impact of parallel pathways of drug elimination and multiple cytochrome P450 involvement on drug-drug interactions: CYP2D6 paradigm. Drug Metab. Dispos. 33(6):837-844 (2005).
8. A. Galetin, H. Burt, L. Gibbons, and J. B. Houston. Prediction of time-dependent CYP3A4 drug-drug interactions: impact of enzyme degradation, parallel elimination pathways, and intestinal inhibition. Drug Metab. Dispos. 34(1):166-175 (2006).
9. R. S. Obach, R. L. Walsky, K. Venkatakrishnan, E. A. Gaman, J. B. Houston, and L. M. Tremaine. The utility of in vitro cytochrome P450 inhibition data in the prediction of drug-drug interactions. J. Pharmacol. Exp. Ther. 316(1):336-348 (2006).
10. J. S. Wang, M. Neuvonen, X. Wen, J. T. Backman, and P. J. Neuvonen. Gemfibrozil inhibits CYP2C8-mediated cerivastatin metabolism in human liver microsomes. Drug Metab. Dispos. 30(12):1352-1356 (2002).
11. Y. Shitara, M. Hirano, H. Sato and Y. Sugiyama. 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(1):228-236 (2004).
12. L. I. Kajosaari, J. Laitila, P. J. Neuvonen, and J. T. Backman. Metabolism of repaglinide by CYP2C8 and CYP3A4 in vitro: effect of fibrates and rifampicin. Basic Clin. Pharmacol. Toxicol. 97(4):249-256 (2005).
13. X. Wen, J. S. Wang, J. T. Backman, K. T. Kivisto, and P. J. Neuvonen. Gemfibrozil is a potent inhibitor of human cytochrome P450 2C9. Drug Metab. Dispos. 29(11):1359-1361 (2001).
14. T. Prueksaritanont, C. Tang, Y. Qiu, L. Mu, R. Subramanian, and J. H. Lin. Effects of fibrates on metabolism of statins in human hepatocytes. Drug Metab. Dispos. 30(11):1280-1287 (2002).
15. J. T. Backman, C. Kyrklund, M. Neuvonen, and P. J. Neuvonen. Gemfibrozil greatly increases plasma concentrations of cerivastatin. Clin. Pharmacol. Ther. 72(6):685-691 (2002).
16. M. Niemi, J. T. Backman, M. Neuvonen, and P. J. Neuvonen. Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: potentially hazardous interaction between gemfibrozil and repaglinide. Diabetologia 46(3):347-351 (2003).
17. D. W. Schneck, B. K. Birmingham, J. A. Zalikowski, P. D. Mitchell, Y. Wang, P. D. Martin, K. C. Lasseter, C. D. Brown, A. S. Windass, and A. Raza. The effect of gemfibrozil on the pharmacokinetics of rosuvastatin. Clin. Pharmacol. Ther. 75(5):455-463 (2004).
18. J. J. Lilja, J. T. Backman, and P. J. Neuvonen. Effect of gemfibrozil on the pharmacokinetics and pharmacodynamics of racemic warfarin in healthy subjects. Br. J. Clin. Pharmacol. 59(4):433-439 (2005).
19. M. Niemi, P. J. Neuvonen, and K. T. Kivisto. Effect of gemfibrozil on the pharmacokinetics and pharmacodynamics of glimepiride. Clin. Pharmacol. Ther. 70(5):439-445 (2001).
20. J. T. Backman, H. Luurila, M. Neuvonen, and P. J. Neuvonen. Rifampin markedly decreases and gemfibrozil increases the plasma concentrations of atorvastatin and its metabolites. Clin. Pharmacol. Ther. 78(2):154-167 (2005).
21. B. W. Ogilvie, D. Zhang, W. Li, A. D. Rodrigues, A. E. Gipson, J. Holsapple, P. Toren, and A. Parkinson. Glucuronidation converts gemfibrozil to a potent, metabolism-dependent inhibitor of CYP2C8: implications for drug-drug interactions. Drug Metab. Dispos. 34(1):191-197 (2006).
22. M. Niemi, J. T. Backman, L. I. Kajosaari, J. B. Leathart, M. Neuvonen, A. K. Daly, M. Eichelbaum, K. T. Kivisto, and P. J. Neuvonen. Polymorphic organic anion transporting polypeptide 1B1 is a major determinant of repaglinide pharmacokinetics. Clin..Pharmacol. Ther. 77(6):468-478 (2005).
23. M. Hirano, K. Maeda, Y. Shitara, and Y. Sugiyama. Drug-drug interaction between pitavastatin and various drugs via oatp1b1. Drug Metab. Dispos. 34(7):1229-1236 (2006).
24. K. Maeda, I. Ieiri, K. Yasuda, A. Fujino, H. Fujiwara, K. Otsubo, M. Hirano, T. Watanabe, Y. Kitamura, K. Kusuhara, and Y. Sugiyama. Effects of organic anion transporting polypeptide 1B1 haplotype on pharmacokinetics of pravastatin, valsartan, and temocapril. Clin. Pharmacol. Ther. 79(5):427-439 (2006).
25. Y. Y. Lau, Y. Huang, L. Frassetto, and L. Z. Benet. Effect of OATP1B transporter inhibition on the pharmacokinetics of atorvastatin in healthy volunteers. Clin. Pharmacol. Ther. 81(2):194-204 (2007).
26. C. Kyrklund, J. T. Backman, K. T. Kivisto, M. Neuvonen, J. Laitila, and P. J. Neuvonen. Plasma concentrations of active lovastatin acid are markedly increased by gemfibrozil but not by bezafibrate. Clin. Pharmacol. Ther. 69(5):340-345 (2001).
27. T. Jaakkola, J. T. Backman, M. Neuvonen, and P. J. Neuvonen. Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics of pioglitazone. Clin. Pharmacol. Ther. 77(5):404-14 (2005).
28. L. J. Deng, F. Wang, and H. D. Li. Effect of gemfibrozil on the pharmacokinetics of pioglitazone. Eur. J. Clin. Pharmacol. 61(11):831-836 (2005).
29. C. Kyrklund, J. T. Backman, M. Neuvonen, and P. J. Neuvonen. Gemfibrozil increases plasma pravastatin concentrations and reduces pravastatin renal clearance. Clin. Pharmacol. Ther. 73(6):538-544 (2003).
30. M. Niemi, J. T. Backman, M. Granfors, J. Laitila, M. Neuvonen, and P. J. Neuvonen. Gemfibrozil considerably increases the plasma concentrations of rosiglitazone. Diabetologia 46(10):1319-1323 (2003).
31. J. T. Backman, C. Kyrklund, K. T. Kivisto, J. S. Wang, and P. J. Neuvonen. Plasma concentrations of active simvastatin acid are increased by gemfibrozil. Clin. Pharmacol. Ther. 68(2):122-129 (2000).
32. M. Niemi, A. Tornio, M. K. Pasanen, H. Fredrikson, P. J. Neuvonen, and J. T. Backman. Itraconazole, gemfibrozil and their combination markedly raise the plasma concentrations of loperamide. Eur. J. Clin. Pharmacol. 62:463-472 (2006).
33. A. Tornio, P. J. Neuvonen, and J. T. Backman. The CYP2C8 inhibitor gemfibrozil does not increase the plasma concentrations of zopiclone. Eur. J. Clin. Pharmacol. 62:645-651 (2006).
34. T. Jaakkola, J. Laitila, P. J. Neuvonen, and J. T. Backman. Pioglitazone is metabolised by CYP2C8 and CYP3A4 in vitro: potential for interactions with CYP2C8 inhibitors. Basic Clin. Pharmacol. Toxicol. 99:44-51 (2006).
35. K. A. Kim, J. Chung, D. H. Jung, and J. Y. Park. Identification of cytochrome P450 isoforms involved in the metabolism of loperamide in human liver microsomes. Eur. J. Clin. Pharmacol. 60:575-581 (2004).
36. F. Ghanbari, K. Rowland-Yeo, J. C. Bloomer, S. E. Clarke, M. S. Lennard, G. T. Tucker, and A. Rostami-Hodjegan. A critical evaluation of the experimental design of studies of mechanism based enzyme inhibition, with implications for in vitro-in vivo extrapolation. Curr. Drug Metab. 7(3):315-334 (2006).
37. N. J. Hassan, D. J. Pountney, C. Ellis, D. E. Mossakowska. BacMam recombinant baculovirus in transporter expression: a study of BCRP and OATP1B1. Protein Expr. Purif. 47(2):591-8 (2006).
38. L. Sabordo, B. C. Sallustio, A. M. Evans, and R. L. Nation. 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(2):414-420 (1999).
39. T. D. Bjornsson, J. T. Callaghan, H. J. Einolf, V. Fischer, L. Gan, S. Grimm, J. Kao, S. P. King, G. Miwa, L. Ni, G. Kumar, J. McLeod, R. S. Obach, S. Roberts, A. Roe, A. Shah, F. Snikeris, J. T. Sullivan, D. Tweedie, J. M. Vega, J. Walsh, and S. A. Wrighton. The conduct of in vitro and in vivo drug-drug interaction studies: a Pharmaceutical Research and Manufacturers of America (PhRMA) perspective. Drug Metab. Dispos. 31(7):815-832 (2003).
40. P. Mathew, T. Cuddy, W. G. Tracewell, and D. Salazar. 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. 75:P33-P33 (2004).
41. C. Olbricht, C. Wanner, T. Eisenhauer, V. Kliem, R. Doll, M. Boddaert, P. O'Grady, M. Krekler, B. Mangold, and U. Christians. Accumulation of lovastatin, but not pravastatin, in the blood of cyclosporine-treated kidney graft patients after multiple doses. Clin. Pharmacol. Ther. 62(3):311-321 (1997).
42. A. Asberg, A. Hartmann, E. Fjeldsa, S. Bergan, and H. Holdaas. Bilateral pharmacokinetic interaction between cyclosporine A and atorvastatin in renal transplant recipients. Am. J. Transplant. 1(4):382-6 (2001).
43. S. G. Simonson, A. Raza, P. D. Martin, P. D. Mitchell, J. A. Jarcho, C. D. Brown, A. S. Windass, and D. W. Schneck. Rosuvastatin pharmacokinetics in heart transplant recipients administered an antirejection regimen including cyclosporine. Clin. Pharmacol. Ther. 76(2):167-177 (2004).
44. T. Hasunuma, M. Nakamura, T. Yachi, N. Arisawa, K. Fukushima, H. Iijima. The drug-drug interactions of pitavastatin (NK-104), a novel HMG-CoA reductase inhibitor and cyclosporine. J. Clin. Ther. Med. 19:381-389 (2003).
45. W. Muck, I. Mai, L. Fritsche, K. Ochmann, G. Rohde, S. Unger, A. Johne, S. Bauer, K. Budde, I. Roots, H. H. Neumayer, and J. Kuhlmann. Increase in cerivastatin systemic exposure after single and multiple dosing in cyclosporine-treated kidney transplant recipients. Clin. Pharmacol. Ther. 65(3):251-61 (1999).
46. L. I. Kajosaari, M. Niemi, M. Neuvonen, J. Laitila, P. J. Neuvonen, and J. T. Backman. Cyclosporine markedly raises the plasma concentrations of repaglinide. Clin. Pharmacol. Ther. 78(4):388-399 (2005).
47. D. W. Everett, T. J. Chando, G. C. Didonato, S. M. Singhvi, H. Y. Pan, and S. H. Weinstein. Biotransformation of pravastatin sodium in humans. Drug Metab. Dispos. 19(4):740-748 (1991).
48. Y. Kameyama, K. Yamashita, K. Kobayashi, M. Hosokawa, and K. Chiba. Functional characterization of SLCO1B1 (OATP-C) variants, SLCO1B1*5, SLCO1B1*15 and SLCO1B1*15+C1007G, by using transient expression systems of HeLa and HEK293 cells. Pharmacogenet. Genomics 15(7):513-522 (2005).
49. Y. Y. Lau, H. Okochi, Y. Huang, and L. Z. Benet. Multiple transporters affect the disposition of atorvastatin and its two active hydroxy metabolites: application of in vitro and ex situ systems. J. Pharmacol. Exp. Ther. 316(2):762-771 (2006).
50. R. H. Ho, R. G. Tirona, B. F. Leake, H. Glaeser, W. Lee, C. J. Lemke, Y. Wang, and R. B. Kim. Drug and bile acid transporters in rosuvastatin hepatic uptake: function, expression and pharmacogenetics. Gastroenterology 130:1793-1806 (2006).
51. Y. Shitara and Y. Sugiyama. Pharmacokinetic and pharmacodynamic alterations of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors: drug-drug interactions and interindividual differences in transporter and metabolic enzyme functions. Pharmacol. Ther. 112(1):71-105 (2006).
52. T. M. Polasek, D. J. Elliot, B. C. Lewis, and J. O. Miners. Mechanism-based inactivation of human cytochrome P450 by drugs in vitro. J. Pharmacol. Exp. Ther. 311(3):996-1007 (2004).
53. M. Hirano, K. Maeda, Y. Shitara, and Y. Sugiyama. Contribution of OATP2 (OATP1B1) and OATP8 (OATP1B3) to the hepatic uptake of pitavastatin in humans. J. Pharmacol. Exp. Ther. 311(1):139-146 (2004).
54. N. Isoherranen, K. L. Kunze, K. E. Allen, W. L. Nelson, and K. E. Thummel. Role of itraconazole metabolites in CYP3A4 inhibition. Drug Metab. Dispos. 32:1121-1131 (2004).
55. J. Y. Chien, A. Lucksiri, C. S. Ernest, II, C. Gorski, S. A. Wrighton, and S. D. Hall. Stochastic prediction of CYP3A-mediated inhibition of midazolam clearance by ketoconazole. Drug Metab. Dispos. 34(7):1208-1219 (2006).
56. H. Lennernas. Clinical pharmacokinetics of atorvastatin. Clin. Pharmacokinet. 42:1141-1160 (2003).
57. S. M. Huang, R. Temple, D. C. Throckmorton, and L. J. Lesko. Drug interaction studies: study design, data analysis, and implications for dosing and labeling. Clin. Pharmacol. Ther. 81(2):298-304 (2007).
58. Y. Shitara, T. Horie, and Y. Sugiyama. Transporters as a determinant of drug clearance and tissue distribution. Eur. J. Pharm. Sci. 27(5):425-446 (2006).
59. I. Ieiri, S. Suwannakul, K. Maeda, H. Uchimaru, K. Hashimoto, M. Kimura, H. Fujino, M. Hirano, H. Kusuhara, S. Irie, S. Higuchi, and Y. Sugiyama. SLCO1B1 (OATP1B1, an uptake transporter) and ABCG2 (BCRP, an efflux transporter) variant alleles and pharmacokinetics of pitavastatin in healthy volunteers. Clin. Pharmacol. Ther. In press (2007)
60. K. T. Kivisto and M. Niemi. Influence of drug transporter polymorphisms on pravastatin pharmacokinetics in humans. Pharm. Res. 24(2):239-47 (2007).
61. K. S. Pang and J. R. Gillette. Kinetics of metabolite formation and elimination in the perfused rat liver preparation: differences between the elimination of preformed acetaminophen and acetaminophen formed from phenacetin. J. Pharmacol. Exp. Ther. 207(1):178-194 (1978).
62. L. Liu and K. S. Pang. The roles of transporters and enzymes in hepatic drug processing. Drug Metab. Dispos. 33(1):1-9 (2005).