Gemfibrozil markedly increases the plasma concentrations of montelukast: a previously unrecognized role for CYP2C8 in the metabolism of montelukast

Clin Pharmacol Ther. 2010 Aug;88(2):223-30. doi: 10.1038/clpt.2010.73. Epub 2010 Jun 30.

Abstract

According to available information, montelukast is metabolized by cytochrome P450 (CYP) 3A4 and 2C9. In order to study the significance of CYP2C8 in the pharmacokinetics of montelukast, 10 healthy subjects were administered gemfibrozil 600 mg or placebo twice daily for 3 days, and 10 mg montelukast on day 3, in a randomized, crossover study. Gemfibrozil increased the mean area under the plasma concentration-time curve (AUC)(0-infinity), peak plasma concentration (C(max)), and elimination half-life (t(1/2)) of montelukast 4.5-fold, 1.5-fold, and 3.0-fold, respectively (P < 0.001). After administration of gemfibrozil, the time to reach C(max) (t(max)) of the montelukast metabolite M6 was prolonged threefold (P = 0.005), its AUC(0-7) was reduced by 40% (P = 0.027), and the AUC(0-24) of the secondary metabolite M4 was reduced by >90% (P < 0.001). In human liver microsomes, gemfibrozil 1-O-beta glucuronide inhibited the formation of M6 (but not of M5) from montelukast 35-fold more potently than did gemfibrozil (half-maximal inhibitory concentration (IC(50)) 3.0 and 107 micromol/l, respectively). In conclusion, gemfibrozil markedly increases the plasma concentrations of montelukast, indicating that CYP2C8 is crucial in the elimination of montelukast.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetates / blood
  • Acetates / pharmacokinetics*
  • Adult
  • Anti-Asthmatic Agents / blood
  • Anti-Asthmatic Agents / pharmacokinetics*
  • Area Under Curve
  • Aryl Hydrocarbon Hydroxylases / metabolism*
  • Biotransformation
  • Cross-Over Studies
  • Cytochrome P-450 CYP2C8
  • DNA / genetics
  • Drug Interactions
  • Female
  • Gemfibrozil / adverse effects*
  • Genotype
  • Glucuronides / metabolism
  • Half-Life
  • Humans
  • Hypolipidemic Agents / adverse effects*
  • Leukotriene Antagonists / blood
  • Leukotriene Antagonists / pharmacokinetics*
  • Male
  • Mass Spectrometry
  • Microsomes, Liver / enzymology
  • Microsomes, Liver / metabolism
  • Quinolines / blood
  • Quinolines / pharmacokinetics*
  • Young Adult

Substances

  • Acetates
  • Anti-Asthmatic Agents
  • Glucuronides
  • Hypolipidemic Agents
  • Leukotriene Antagonists
  • Quinolines
  • DNA
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C8 protein, human
  • Cytochrome P-450 CYP2C8
  • montelukast
  • Gemfibrozil