Inhibition of Triazolam Hydroxylation by Ketoconazole, Itraconazole, Hydroxyitraconazole and Fluconazole In‐vitro

The capacity of hydroxyitraconazole, an in-vivo metabolite of the antifungal agent itraconazole, to inhibit human cytochrome P4503A isoforms was evaluated in-vitro using a human microsomal model. Varying concentrations of ketoconazole, itraconazole, hydroxyitraconazole and fluconazole were incubated with human liver microsomes and triazolam (250 μM), an index compound used to profile activity of P4503A isoforms. Formation of α-OH- and 4-OH-triazolam was quantitated by high-performance liquid chromatography. Ketoconazole was the most potent inhibitor of triazolam metabolite formation (mean IC50 0.074–0.076 μM), while fluconazole was less potent (IC50 4.4–4.9 μM). Both itraconazole and hydroxy-itraconazole had similar IC50 values (0.4–0.7 μM), with potency intermediate between ketoconazole and fluconazole. Hydroxyitraconazole may contribute to impaired clearance of P4503A substrates, and consequent pharmacokinetic drug interactions, during treatment with itraconazole in man.