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

Clinical Pharmacology and Therapeutics

Volumn 84, Issue 3, 2008, Pages 403-411

  Tornio, A ^a   Niemi, M ^a   Neuvonen, M ^a   Laitila, J ^a   Kalliokoski, A ^a   Neuvonen, P J ^a   Backman, J T ^a  

^a UNIVERSITY OF HELSINKI   (Finland)

Author keywords

[No Author keywords available]

Indexed keywords

CYTOCHROME P450 2C8; CYTOCHROME P450 3A4; DRUG METABOLITE; GEMFIBROZIL; GEMFIBROZIL 1 O BETA GLUCURONIDE; GLUCOSE; GLUCURONIDE; REPAGLINIDE;

ADULT; AREA UNDER THE CURVE; ARTICLE; CLINICAL TRIAL; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; CROSSOVER PROCEDURE; DRUG BLOOD LEVEL; DRUG EFFECT; DRUG HALF LIFE; ENZYME INHIBITION; FEMALE; GLUCOSE BLOOD LEVEL; HUMAN; HUMAN EXPERIMENT; MALE; NORMAL HUMAN; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; VOLUNTEER;

ADULT; ANTILIPEMIC AGENTS; AREA UNDER CURVE; ARYL HYDROCARBON HYDROXYLASES; BLOOD GLUCOSE; CARBAMATES; DRUG INTERACTIONS; FEMALE; GEMFIBROZIL; GLUCURONATES; HALF-LIFE; HUMANS; HYPOGLYCEMIC AGENTS; MALE; PIPERIDINES;

EID: 49949093994     PISSN: 00099236     EISSN: 15326535     Source Type: Journal    
DOI: 10.1038/clpt.2008.34     Document Type: Article

References (50)

1. Gromada, J., Dissing, S., Kofod, H. & Frøkjaer-Jensen, J. Effects of the hypoglycaemic drugs repaglinide and glibenclamide on ATP-sensitive potassium-channels and cytosolic calcium levels in beta TC3 cells and rat pancreatic beta cells. Diabetologia 38, 1025-1032 (1995).
2. Hatorp, V. Clinical pharmacokinetics and pharmacodynamics of repaglinide. Clin. Pharmacokinet. 41, 471-483 (2002).
3. Hatorp, V., Oliver, S. & Su, C.A. Bioavailability of repaglinide, a novel antidiabetic agent, administered orally in tablet or solution form or intravenously in healthy male volunteers. Int. J. Clin. Pharmacol. Ther. 36, 636-641 (1998).
4. Bidstrup, T.B., Bjørnsdottir, I., Sidelmann, U.G., Thomsen, M.S. & Hansen, K.T. CYP2C8 and CYP3A4 are the principal enzymes involved in the human in vitro biotransformation of the insulin secretagogue repaglinide. Br. J. Clin. Pharmacol. 56, 305-314 (2003).
5. Kajosaari, L.I., Laitila, J., Neuvonen, P.J. & Backman, J.T. Metabolism of repaglinide by CYP2C8 and CYP3A4 in vitro: effect of fibrates and rifampicin. Basic Clin. Pharmacol. Toxicol. 97, 249-256 (2005).
6. Kajosaari, L.I., Niemi, M., Neuvonen, M., Laitila, J., Neuvonen, P.J. & Backman, J.T. Cyclosporine markedly raises the plasma concentrations of repaglinide. Clin. Pharmacol. Ther. 78, 388-399 (2005).
7. Niemi, M., Neuvonen, P.J. & Kivistö, K.T. The cytochrome P4503A4 inhibitor clarithromycin increases the plasma concentrations and effects of repaglinide. Clin. Pharmacol. Ther. 70, 58-65 (2001).
8. Niemi, M., Backman, J.T., Neuvonen, M. & Neuvonen, P.J. 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 (2003).
9. Niemi, M., Kajosaari, L.I., Neuvonen, M., Backman, J.T. & Neuvonen, P.J. The CYP2C8 inhibitor trimethoprim increases the plasma concentrations of repaglinide in healthy subjects. Br. J. Clin. Pharmacol. 57, 441-447 (2004).
10. Kajosaari, L.I., Niemi, M., Backman, J.T. & Neuvonen, P.J. Telithromycin, but not montelukast, increases the plasma concentrations and effects of the cytochrome P450 3A4 and 2C8 substrate repaglinide. Clin. Pharmacol. Ther. 79, 231-242 (2006).
11. Hatorp, V., Hansen, K.T. & Thomsen, M.S. Influence of drugs interacting with CYP3A4 on the pharmacokinetics, pharmacodynamics, and safety of the prandial glucose regulator repaglinide. J. Clin. Pharmacol. 43, 649-660 (2003).
12. Bidstrup, T.B., Damkier, P., Olsen, A.K., Ekblom, M., Karlsson, A. & Brøsen, K. The impact of CYP2C8 polymorphism and grapefruit juice on the pharmacokinetics of repaglinide. Br. J. Clin. Pharmacol. 61, 49-57 (2006).
13. Niemi, M. et al. Polymorphic organic anion transporting polypeptide 1B1 is a major determinant of repaglinide pharmacokinetics. Clin. Pharmacol. Ther. 77, 468-478 (2005).
14. Kalliokoski, A., Neuvonen, M., Neuvonen, P.J. & Niemi, M. Different effects of SLCO1B1 polymorphism on the pharmacokinetics and pharmacodynamics of repaglinide and nateglinide. J. Clin. Pharmacol. 48, 311-321 (2008).
15. Wang, J.S., Neuvonen, M., Wen, X., Backman, J.T. & Neuvonen, P.J. Gemfibrozil inhibits CYP2C8-mediated cerivastatin metabolism in human liver microsomes. Drug Metab. Dispos. 30, 1352-1356 (2002).
16. Backman, J.T., Kyrklund, C., Neuvonen, M. & Neuvonen, P.J. Gemfibrozil greatly increases plasma concentrations of cerivastatin. Clin. Pharmacol. Ther. 72, 685-691 (2002).
17. Niemi, M., Backman, J.T., Granfors, M., Laitila, J., Neuvonen, M. & Neuvonen, P.J. Gemfibrozil considerably increases the plasma concentrations of rosiglitazone. Diabetologia 46, 1319-1323 (2003).
18. Niemi, M., Tornio, A., Pasanen, M.K., Fredrikson, H., Neuvonen, P.J. & Backman, J.T. Itraconazole, gemfibrozil and their combination markedly raise the plasma concentrations of loperamide. Eur. J. Clin. Pharmacol. 62, 463-472 (2006).
19. Jaakkola, T., Backman, J.T., Neuvonen, M. & Neuvonen, P.J. Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics of pioglitazone. Clin. Pharmacol. Ther. 77, 404-414 (2005).
20. Ogilvie, B.W. et al. Glucuronidation converts gemfibrozil to a potent, metabolism-dependent inhibitor of CYP2C8: implications for drug-drug interactions. Drug Metab. Dispos. 34, 191-197 (2006).
21. Shitara, Y., Hirano, M., Sato, H. & Sugiyama, Y. 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 (2004).
22. Yamazaki, M. et al. Effects of fibrates on human organic anion-transporting polypeptide 1B1-, multidrug resistance protein 2- and P-glycoprotein-mediated transport. Xenobiotica 35, 737-753 (2005).
23. Kyrklund, C., Backman, J.T., Neuvonen, M. & Neuvonen, P.J. Gemfibrozil increases plasma pravastatin concentrations and reduces pravastatin renal clearance. Clin. Pharmacol. Ther. 73, 538-544 (2003).
24. Schneck, D.W. et al. The effect of gemfibrozil on the pharmacokinetics of rosuvastatin. Clin. Pharmacol. Ther. 75, 455-463 (2004).
25. Ho, R.H. et al. Drug and bile acid transporters in rosuvastatin hepatic uptake: function, expression, and pharmacogenetics. Gastroenterology 130, 1793-1806 (2006).
26. Prandin prescribing information. 〈http://www.prandin.com/docs/ prandin_insert.pdf〉. Accessed 4 January 2008.
27. Todd, P.A. & Ward, A. Gemfibrozil. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in dyslipidaemia. Drugs 36, 314-339 (1988).
28. Backman, J.T., Kyrklund, C., Kivistö, K.T., Wang, J.S. & Neuvonen, P.J. Plasma concentrations of active simvastatin acid are increased by gemfibrozil. Clin. Pharmacol. Ther. 68, 122-129 (2000).
29. Backman, J.T., Luurila, H., Neuvonen, M. & Neuvonen, P.J. Rifampin markedly decreases and gemfibrozil increases the plasma concentrations of atorvastatin and its metabolites. Clin. Pharmacol. Ther. 78, 154-167 (2005).
30. Niemi, M., Pasanen, M.K. & Neuvonen, P.J. SLCO1B1 polymorphism and sex affect the pharmacokinetics of pravastatin but not fluvastatin. Clin. Pharmacol. Ther. 80, 356-366 (2006).
31. Pasanen, M.K., Neuvonen, M., Neuvonen, P.J. & Niemi, M. SLCO1B1 polymorphism markedly affects the pharmacokinetics of simvastatin acid. Pharmacogenet. Genomics 16, 873-879 (2006).
32. Pasanen, M.K., Fredrikson, H., Neuvonen, P.J. & Niemi, M. Different effects of SLCO1B1 polymorphism on the pharmacokinetics of atorvastatin and rosuvastatin. Clin. Pharmacol. Ther. 82, 726-733 (2007).
33. Niemi, M., Leathart, J.B., Neuvonen, M., Backman, J.T., Daly, A.K. & Neuvonen, P.J. Polymorphism in CYP2C8 is associated with reduced plasma concentrations of repaglinide. Clin. Pharmacol. Ther. 74, 380-387 (2003).
34. Ghanbari, F. et al. 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, 315-334 (2006).
35. Kunze, K.L. & Trager, W.F. Isoform-selective mechanism-based inhibition of human cytochrome P450 1A2 by furafylline. Chem. Res. Toxicol. 6, 649-656 (1993).
36. Karjalainen, M.J., Neuvonen, P.J. & Backman, J.T. Rofecoxib is a potent, metabolism-dependent inhibitor of CYP1A2: implications for in vitro prediction of drug interactions. Drug Metab. Dispos. 34, 2091-2096 (2006).
37. Richter, T. et al. Potent mechanism-based inhibition of human CYP2B6 by clopidogrel and ticlopidine. J. Pharmacol. Exp. Ther. 308, 189-197 (2004).
38. Turpeinen, M., Tolonen, A., Uusitalo, J., Jalonen, J., Pelkonen, O. & Laine, K. Effect of clopidogrel and ticlopidine on cytochrome P450 2B6 activity as measured by bupropion hydroxylation. Clin. Pharmacol. Ther. 77,553-559 (2005).
39. Bertelsen, K.M., Venkatakrishnan, K., Von Moltke, L.L., Obach, R.S. & Greenblatt, D.J. Apparent mechanism-based inhibition of human CYP2D6 in vitro by paroxetine: comparison with fluoxetine and quinidine. Drug Metab. Dispos. 31, 289-293 (2003).
40. Venkatakrishnan, K. & Obach, R.S. In vitro-in vivo extrapolation of CYP2D6 inactivation by paroxetine: prediction of nonstationary pharmacokinetics and drug interaction magnitude. Drug Metab. Dispos. 33, 845-852 (2005).
41. Periti, P., Mazzei, T., Mini, E. & Novelli, A. Pharmacokinetic drug interactions of macrolides. Clin. Pharmacokinet. 23, 106-131 (1992).
42. Schmiedlin-Ren, P. et al. Mechanisms of enhanced oral availability of CYP3A4 substrates by grapefruit constituents. Decreased enterocyte CYP3A4 concentration and mechanism-based inactivation by furanocoumarins. Drug Metab. Dispos. 25, 1228-1233 (1997).
43. Lilja, J.J., Kivistö, K.T. & Neuvonen, P.J. Duration of effect of grapefruit juice on the pharmacokinetics of the CYP3A4 substrate simvastatin. Clin. Pharmacol. Ther. 68, 384-390 (2000).
44. Liston, H.L., DeVane, C.L., Boulton, D.W., Risch, S.C., Markowitz, J.S. & Goldman, J. Differential time course of cytochrome P450 2D6 enzyme inhibition by fluoxetine, sertraline, and paroxetine in healthy volunteers. J. Clin. Psychopharmacol. 22, 169-173 (2002).
45. Renwick, A.B. et al. Differential maintenance of cytochrome P450 enzymes in cultured precision-cut human liver slices. Drug Metab. Dispos. 28, 1202-1209 (2000).
46. Sallustio, B.C., Fairchild, B.A., Shanahan, K., Evans, A.M. & Nation, R.L. Disposition of gemfibrozil and gemfibrozil acyl glucuronide in the rat isolated perfused liver. Drug Metab. Dispos. 24, 984-989 (1996).
47. Sabordo, L., Sallustio, B.C., Evans, A.M. & Nation, R.L. Hepatic disposition of the acyl glucuronide 1-O-gemfibrozil-beta-D-glucuronide: effects of dibromosulfophthalein on membrane transport and aglycone formation. J. Pharmacol. Exp. Ther. 288, 414-420 (1999).
48. Hinton, L.K., Galetin, A. & Houston, J.B. Multiple inhibition mechanisms and prediction of drug-drug interactions: status of metabolism and transporter models as exemplified by gemfibrozil-drug interactions. Pharm. Res., epub ahead of print (2007).
49. Thomas, B.F., Burgess, J.P., Coleman, D.P., Scheffler, N.M., Jeffcoat, A.R. & Dix, K.J. Isolation and identification of novel metabolites of gemfibrozil in rat urine. Drug Metab. Dispos. 27, 147-157 (1999).
50. Pasanen, M.K., Backman, J.T., Neuvonen, P.J. & Niemi, M. Frequencies of single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide 1B1 SLCO1B1 gene in a Finnish population. Eur. J. Clin. Pharmacol. 62, 409-415 (2006).