期刊
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
卷 53, 期 2, 页码 541-551出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.01123-08
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资金
- National Institute of General Medical Sciences, National Institutes of Health (Bethesda, MD [5R01GM078501-02, 2R56GM067308-09A1, T32GM008425]
- Research Institute of Medical Science of Chonnam National University, Gwangju, South Korea
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 mu M); its effect on CYP1A2, CYP2A6, CYP2C8, and CYP2D6 was marginal (< 25% inhibition at 100 mu M voriconazole). Further detailed experiments with HLMs showed that voriconazole is a potent competitive inhibitor of CYP2B6 (K-i < 0.5), CYP2C9 (K-i = 2.79 mu M), and CYP2C19 (K-i = 5.1 mu M). The inhibition of CYP3A by voriconazole was explained by noncompetitive (K-i = 2.97 mu M) and competitive (K-i = 0.66 mu M) 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.
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