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Antimicrobial Agents and Chemotherapy, February 2009, p. 541-551, Vol. 53, No. 2
0066-4804/09/$08.00+0     doi:10.1128/AAC.01123-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Comprehensive In Vitro Analysis of Voriconazole Inhibition of Eight Cytochrome P450 (CYP) Enzymes: Major Effect on CYPs 2B6, 2C9, 2C19, and 3A{triangledown}

Seongwook Jeong,{dagger} Phuong D. Nguyen, and Zeruesenay Desta*

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

Received 21 August 2008/ Returned for modification 28 September 2008/ Accepted 15 November 2008

Voriconazole is an effective antifungal drug, but adverse drug-drug interactions associated with its use are of major clinical concern. To identify the mechanisms of these interactions, we tested the inhibitory potency of voriconazole with eight human cytochrome P450 (CYP) enzymes. Isoform-specific probes were incubated with human liver microsomes (HLMs) (or expressed CYPs) and cofactors in the absence and the presence of voriconazole. Preincubation experiments were performed to test mechanism-based inactivation. In pilot experiments, voriconazole showed inhibition of CYP2B6, CYP2C9, CYP2C19, and CYP3A (half-maximal [50%] inhibitory concentrations, <6 µM); its effect on CYP1A2, CYP2A6, CYP2C8, and CYP2D6 was marginal (<25% inhibition at 100 µM voriconazole). Further detailed experiments with HLMs showed that voriconazole is a potent competitive inhibitor of CYP2B6 (Ki < 0.5), CYP2C9 (Ki = 2.79 µM), and CYP2C19 (Ki = 5.1 µM). The inhibition of CYP3A by voriconazole was explained by noncompetitive (Ki = 2.97 µM) and competitive (Ki = 0.66 µM) modes of inhibition. Prediction of the in vivo interaction of voriconazole 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.

* Corresponding author. Mailing address: Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, 1001 West 10th Street, WD Myers Bldg., W7123, Indianapolis, IN 46202. Phone: (317) 630-8860. Fax: (317) 630-8185. E-mail: zdesta{at}iupui.edu

{triangledown} Published ahead of print on 24 November 2008.

{dagger} Present address: Department of Anesthesiology, Chonnam University Medical School Gwangju, South Korea.

Antimicrobial Agents and Chemotherapy, February 2009, p. 541-551, Vol. 53, No. 2
0066-4804/09/$08.00+0     doi:10.1128/AAC.01123-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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