Purpose: Zafirlukast is a substrate of cytochrome P450 2C9 (CYP2C9) and cytochrome P450 3A4 (CYP3A4) in vitro, but the role of these enzymes in its metabolism in vivo is unknown. To investigate the contribution of CYP2C9 and CYP3A4 to zafirlukast metabolism, we studied the effects of fluconazole and itraconazole on its pharmacokinetics (PK).
Methods: In a randomized crossover study, 12 healthy volunteers ingested fluconazole 200 mg (first dose 400 mg) once daily, itraconazole 100 mg (first dose 200 mg) twice daily, or placebo twice daily for 5 days, and on day 3, 20 mg zafirlukast. Plasma concentrations of zafirlukast and the antimycotics were measured up to 72 h.
Results: Fluconazole increased the total area under the plasma concentration-time curve (AUC) of zafirlukast 1.6-fold [95% confidence interval (CI) 1.3-2.0-fold, P < 0.001), and its peak plasma concentration 1.5-fold (95% CI 1.2-2.0-fold, P < 0.05). Fluconazole did not affect the time of peak plasma concentration or elimination half-life of zafirlukast. None of the zafirlukast PK variables differed significantly from the control in the itraconazole phase; e.g., the ratio to control of the total AUC of zafirlukast was 1.0 (95% CI 0.82-1.2) during the itraconazole phase.
Conclusions: Fluconazole, but not itraconazole, increases zafirlukast plasma concentrations, strongly suggesting that CYP2C9 but not CYP3A4 participates in zafirlukast metabolism in humans.