Objective: Pioglitazone, a thiazolidinedione antidiabetic drug, is metabolised mainly by the cytochrome P450 (CYP) 2C8 enzyme. The leukotriene receptor antagonists montelukast and zafirlukast have potently inhibited CYP2C8 activity and the metabolism of pioglitazone in vitro. Our objective was to determine whether montelukast and zafirlukast increase the plasma concentrations of pioglitazone in humans.
Methods: In a randomised, double-blind crossover study with three phases and a washout period of 3 weeks, 12 healthy volunteers took either 10 mg montelukast once daily and placebo once daily, or 20 mg zafirlukast twice daily, or placebo twice daily, for 6 days. On day 3, they received a single oral dose of 15 mg pioglitazone. The plasma concentrations of pioglitazone and its metabolites M-IV, M-III, M-V and M-XI were measured for 96 h.
Results: The total area under the plasma concentration-time curve of pioglitazone during the montelukast and zafirlukast phases was 101% (range 71-143%) and 103% (range 78-146%), respectively, of that during the placebo phase. Also, the peak plasma concentration and elimination half-life of pioglitazone remained unaffected by montelukast and zafirlukast. There were no statistically significant differences in the pharmacokinetics of any of the metabolites of pioglitazone between the phases.
Conclusions: Montelukast and zafirlukast do not increase the plasma concentrations of pioglitazone, indicating that their inhibitory effect on CYP2C8 is negligible in vivo, despite their strong inhibitory effect on CYP2C8 in vitro. The results highlight the importance of in vivo interaction studies and of the incorporation of relevant pharmacokinetic properties of drugs, including plasma protein binding data, to in vitro-in vivo interaction predictions.