CYP2C8 but not CYP3A4 is important in the pharmacokinetics of montelukast

Br J Clin Pharmacol. 2012 Feb;73(2):257-67. doi: 10.1111/j.1365-2125.2011.04086.x.


Aim: According to product information, montelukast is extensively metabolized by CYP3A4 and CYP2C9. However, CYP2C8 was also recently found to be involved. Our aim was to study the effects of selective CYP2C8 and CYP3A4 inhibitors on the pharmacokinetics of montelukast.

Methods: In a randomized crossover study, 11 healthy subjects ingested gemfibrozil 600 mg, itraconazole 100 mg (first dose 200 mg) or both, or placebo twice daily for 5 days, and on day 3, 10 mg montelukast. Plasma concentrations of montelukast, gemfibrozil, itraconazole and their metabolites were measured up to 72 h.

Results: The CYP2C8 inhibitor gemfibrozil increased the AUC(0,∞) of montelukast 4.3-fold and its t(1/2) 2.1-fold (P < 0.001). Gemfibrozil impaired the formation of the montelukast primary metabolite M6, reduced the AUC and C(max) of the secondary (major) metabolite M4 by more than 90% (P < 0.05) and increased those of M5a and M5b (P < 0.05). The CYP3A4 inhibitor itraconazole had no significant effect on the pharmacokinetic variables of montelukast or its M6 and M4 metabolites, but markedly reduced the AUC and C(max) of M5a and M5b (P < 0.05). The effects of the gemfibrozil-itraconazole combination on the pharmacokinetics of montelukast did not differ from those of gemfibrozil alone.

Conclusions: CYP2C8 is the dominant enzyme in the biotransformation of montelukast in humans, accounting for about 80% of its metabolism. CYP3A4 only mediates the formation of the minor metabolite M5a/b, and is not important in the elimination of montelukast. Montelukast may serve as a safe and useful CYP2C8 probe drug.

Publication types

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

MeSH terms

  • 14-alpha Demethylase Inhibitors / pharmacology*
  • Acetates / pharmacokinetics*
  • Adult
  • Anti-Asthmatic Agents / pharmacokinetics*
  • Area Under Curve
  • Aryl Hydrocarbon Hydroxylases / physiology*
  • Cross-Over Studies
  • Cytochrome P-450 CYP2C8
  • Cytochrome P-450 CYP3A / physiology*
  • Drug Interactions
  • Female
  • Gemfibrozil / pharmacology
  • Humans
  • Hypolipidemic Agents / pharmacology*
  • Itraconazole / pharmacology
  • Male
  • Quinolines / pharmacokinetics*
  • Young Adult


  • 14-alpha Demethylase Inhibitors
  • Acetates
  • Anti-Asthmatic Agents
  • Hypolipidemic Agents
  • Quinolines
  • Itraconazole
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C8 protein, human
  • Cytochrome P-450 CYP2C8
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • montelukast
  • Gemfibrozil