Gemfibrozil markedly increases the plasma concentrations of montelukast: A previously unrecognized role for CYP2c8 in the metabolism of montelukast

Clinical Pharmacology and Therapeutics

Volumn 88, Issue 2, 2010, Pages 223-230

  Karonen, T ^a   Filppula, A ^a   Laitila, J ^a   Niemi, M ^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; DRUG METABOLITE; GEMFIBROZIL; GLUCURONIDE; MONTELUKAST; PLACEBO;

ADULT; AREA UNDER THE CURVE; ARTICLE; CLINICAL TRIAL; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; CROSSOVER PROCEDURE; DRUG BLOOD LEVEL; DRUG EFFECT; DRUG ELIMINATION; DRUG HALF LIFE; DRUG INHIBITION; DRUG METABOLISM; FEMALE; HUMAN; HUMAN EXPERIMENT; IC 50; LIVER MICROSOME; LIVER MICROSOME METABOLISM; MALE; MAXIMUM PLASMA CONCENTRATION; PHASE 2 CLINICAL TRIAL; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; SINGLE DRUG DOSE; TIME TO MAXIMUM PLASMA CONCENTRATION;

ACETATES; ADULT; ANTI-ASTHMATIC AGENTS; ANTILIPEMIC AGENTS; AREA UNDER CURVE; ARYL HYDROCARBON HYDROXYLASES; BIOTRANSFORMATION; CROSS-OVER STUDIES; DNA; DRUG INTERACTIONS; FEMALE; GEMFIBROZIL; GENOTYPE; GLUCURONIDES; HALF-LIFE; HUMANS; LEUKOTRIENE ANTAGONISTS; MALE; MASS SPECTROMETRY; MICROSOMES, LIVER; QUINOLINES; YOUNG ADULT;

EID: 77954887450     PISSN: 00099236     EISSN: 15326535     Source Type: Journal    
DOI: 10.1038/clpt.2010.73     Document Type: Article

References (34)

1. Reiss, T.F. et al. Efects of montelukast (MK-0476), a new potent cysteinyl leukotriene (LtD4) receptor antagonist, in patients with chronic asthma. J. Allergy Clin. Immunol. 98, 528-534 (1996).
2. Altman, L.C. et al. A placebo-controlled, dose-ranging study of montelukast, a cysteinyl leukotriene-receptor antagonist. Montelukast Asthma study group. J. Allergy Clin. Immunol. 102, 50-56 (1998).
3. Knorr, B. et al. Montelukast for chronic asthma in 6-to 14-year-old children: a randomized, double-blind trial. Pediatric Montelukast study group. JAMA 279, 1181-1186 (1998).
4. Lipworth, B.J. Leukotriene-receptor antagonists. Lancet 353, 57-62 (1999).
5. Reiss, T.F., Chervinsky, P., Dockhorn, R.J., shingo, S., seidenberg, B. & Edwards, T.B. Montelukast, a once-daily leukotriene receptor antagonist, in the treatment of chronic asthma: a multicenter, randomized, double-blind trial. Montelukast Clinical Research study group. Arch. Intern. Med. 158, 1213-1220 (1998).
6. Cheng, H. et al. Pharmacokinetics, bioavailability, and safety of montelukast sodium (MK-0476) in healthy males and females. Pharm. Res. 13, 445-448 (1996).
7. Balani, S.K. et al. Metabolic profles of montelukast sodium (singulair) a potent cysteinyl leukotriene1 receptor antagonist, in human plasma and bile. Drug Metab. Dispos. 25 1282-1287 1997). singulair [label]. Whitehouse station, NJ: Merck 2009 〈http://www.accessdata.fda.gov/drugsatfda-docs/label/2009/ 020829s051-020830s052-021409s028lbl.pdf
8. Chiba, M., Xu, X., Nishime, J.A., Balani, S.K. & Lin, J.H. Hepatic microsomal metabolism of montelukast, a potent leukotriene D4 receptor antagonist, in humans. Drug Metab. Dispos. 25, 1022-1031 (1997).
9. Walsky, R.L., Obach, R.S., gaman, E.A., gleeson, J.P. & Proctor, W.R. selective inhibition of human cytochrome P4502C8 by montelukast. Drug Metab. Dispos. 33, 413-418 (2005).
10. Walsky, R.L., gaman, E.A. & Obach, R.S. Examination of 209 drugs for inhibition of cytochrome P450 2C8. J. Clin. Pharmacol. 45, 68-78 (2005)
11. Jaakkola, T., Laitila, J., Neuvonen, P.J. & Backman, J.T. Pioglitazone is metabolised by CYP2C8 and CYP3A4 in vitro: potential for interactions with CYP2C8 inhibitors. Basic Clin. Pharmacol. Toxicol. 99, 44-51 (2006)
12. Jaakkola, T., Backman, J.T., Neuvonen, M., Niemi, M. & Neuvonen, P.J. Montelukast and zafrlukast do not afect the pharmacokinetics of the CYP2C8 substrate pioglitazone. Eur. J. Clin. Pharmacol. 62, 503-509 (2006).
13. Kajosaari, L.I., Niemi, M., Backman, J.T. & Neuvonen, P.J. telithromycin, but not montelukast, increases the plasma concentrations and efects of the cytochrome P450 3A4 and 2C8 substrate repaglinide. Clin. Pharmacol. Ther. 79, 231-242 (2006).
14. Kim, K.A., Park, P.W., Kim, K.R. & Park, J.Y. Efect of multiple doses of montelukast on the pharmacokinetics of rosiglitazone, a CYP2C8 substrate, in humans. Br. J. Clin. Pharmacol. 63, 339-345 (2007)
15. Shitara, Y., Hirano, M., sato, H. & sugiyama, Y. gemfbrozil 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 gemfbrozil. J. Pharmacol. Exp. Ther. 311, 228-236 (2004).
16. Ogilvie, B.W. et al. glucuronidation converts gemfbrozil to a potent, metabolism-dependent inhibitor of CYP2C8: implications for drug-drug interactions. Drug Metab. Dispos. 34, 191-197 (2006).
17. Baer, B.R., DeLisle, R.K. & Allen, A. Benzylic oxidation of gemfbrozil-1-O-β-glucuronide by P450 2C8 leads to heme alkylation and irreversible inhibition. Chem. Res. Toxicol. 22, 1298-1309 (2009).
18. Tornio, A. et al. the efect of gemfbrozil 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 (2008).
19. Backman, J.T. et al. CYP2C8 activity recovers within 96 hours after gemfbrozil dosing: estimation of CYP2C8 half-life using repaglinide as an in vivo probe. Drug Metab. Dispos. 37, 2359-2366 (2009).
20. Niemi, M., Backman, J.T., Neuvonen, M. & Neuvonen, P.J. Efects of gemfbrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: potentially hazardous interaction between gemfbrozil and repaglinide. Diabetologia 46, 347-351 (2003)
21. Backman, J.T., Kyrklund, C., Neuvonen, M. & Neuvonen, P.J. gemfbrozil greatly increases plasma concentrations of cerivastatin. Clin. Pharmacol. Ther. 72, 685-691 (2002).
22. Neuvonen, P.J., Niemi, M. & Backman, J.T. Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin. Pharmacol. Ther. 80, 565-581 (2006).
23. Wen, X., Wang, J.S., Backman, J.T., Kivistö, K.T. & Neuvonen, P.J. gemfbrozil is a potent inhibitor of human cytochrome P450 2C9. Drug Metab. Dispos. 29, 1359-1361 (2001)
24. Wang, J.S., Neuvonen, M., Wen, X., Backman, J.T. & Neuvonen, P.J. gemfbrozil inhibits CYP2C8-mediated cerivastatin metabolism in human liver microsomes. Drug Metab. Dispos. 30, 1352-1356 (2002).
25. Lilja, J.J., Backman, J.T. & Neuvonen, P.J. Efect of gemfbrozil on the pharmacokinetics and pharmacodynamics of racemic warfarin in healthy subjects. Br. J. Clin. Pharmacol. 59, 433-439 (2005)
26. Schoch, G.A., Yano, J.K., sansen, S., Dansette, P.M., stout, C.D. & Johnson, E.F. Determinants of cytochrome P450 2C8 substrate binding: structures of complexes with montelukast, troglitazone, felodipine, and 9-cis-retinoic acid. J. Biol. Chem. 283, 17227-17237 (2008).
27. Us Food and Drug Administration. Center for Drug Evaluation and Research. Pharmacology Review(s) for singulair (January 1998)
28. Schoch, G.A., Yano, J.K., Wester, M.R., grifn, K.J., stout, C.D. & Johnson, E.F. structure of human microsomal cytochrome P450 2C8. Evidence for a peripheral fatty acid binding site. J. Biol. Chem. 279, 9497-9503 (2004).
29. Mougey, E.B., Feng, H., Castro, M., Irvin, C.G. & Lima, J.J. Absorption of montelukast is transporter mediated: a common variant of OAtP2B1 is associated with reduced plasma concentrations and poor response. Pharmacogenet. Genomics 19, 129-138 (2009).
30. Niemi, M. Role of OAtP transporters in the disposition of drugs. Pharmacogenomics 8, 787-802 (2007)
31. Shitara, Y., sato, H. & sugiyama, Y. Evaluation of drug-drug interaction in the hepatobiliary and renal transport of drugs. Annu. Rev. Pharmacol. Toxicol. 45, 689-723 (2005).
32. Ho, R.H. et al. Drug and bile acid transporters in rosuvastatin hepatic uptake: function, expression, and pharmacogenetics. Gastroenterology 130, 1793-1806 (2006).
33. Kivistö, K.T. et al. Lipid-lowering response to statins is afected by CYP3A5 polymorphism. Pharmacogenetics 14, 523-525 (2004).
34. Kalliokoski, A., Neuvonen, M., Neuvonen, P.J. & Niemi, M. Diferent efects of sLCO1B1 polymorphism on the pharmacokinetics and pharmacodynamics of repaglinide and nateglinide. J. Clin. Pharmacol. 48, 311-321 (2008).