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Antimicrob. Agents Chemother. doi:10.1128/AAC.01123-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Comprehensive in vitro inhibition analysis of 8 cytochrome P450 (CYP) enzymes by voriconazole: major effect on CYPs 2B6, 2C9, 2C19 and 3A

Division of Clinical Pharmacology, Department of Medicine, Indiana University, Indianapolis, USA

^* To whom correspondence should be addressed. Email: zdesta{at}iupui.edu.

	Abstract

Voriconazole is an effective antifungal drug, but adverse drug-drug interactions associated with its use are of major clinical concern. To identify mechanisms of these interactions, we tested the inhibitory potency of voriconazole on 8 human cytochrome P450 (CYP) enzymes. Isoform specific probes were incubated with human liver microsomes (HLMs) (or expressed CYPs) and cofactors in the absence and presence of voriconazole. Preincubation experiments were performed to test mechanism-based inactivation. In pilot experiments, voriconazole showed inhibition of CYP2B6, CYP2C9, CYP2C19 and CYP3A (IC50s values, <6µM); its effect on CYP1A2, CYP2A6, CYP2C8 and CYP2D6 was marginal (inhibition <25% at 100µM voriconazole). Further detailed experiments in HLMs show that voriconazole is a potent competitive inhibitor of CYP2B6 (K_i<0.5), CYP2C9 (K_i = 2.79µM) and CYP2C19 (K_i = 5.1 µM). The inhibition of CYP3A by voriconazole was explained by noncompetitive (K_i = 2.97 µM) and competitive (K_i = 0.66 µM) mode of inhibition. In vivo prediction from these in vitro data suggests that voriconazole would substantially increase the exposure of drugs metabolized by CYP2B6, CYP2C9, CYP2C19 and CYP3A. Clinicians should be aware of these interactions and monitor patients for adverse effects or failure of therapy.