Comprehensive in vitro analysis of voriconazole inhibition of eight cytochrome P450 (CYP) enzymes: major effect on CYPs 2B6, 2C9, 2C19, and 3A.
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Jeong S, Nguyen PD, Desta Z
Comprehensive in vitro analysis of voriconazole inhibition of eight cytochrome P450 (CYP) enzymes: major effect on CYPs 2B6, 2C9, 2C19, and 3A.
Antimicrob Agents Chemother. 2009 Feb;53(2):541-51. doi: 10.1128/AAC.01123-08. Epub 2008 Nov 24.
- PubMed ID
- 19029318 [ View in PubMed]
- Abstract
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 microM); its effect on CYP1A2, CYP2A6, CYP2C8, and CYP2D6 was marginal (<25% inhibition at 100 microM 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 microM), and CYP2C19 (K(i) = 5.1 microM). The inhibition of CYP3A by voriconazole was explained by noncompetitive (K(i) = 2.97 microM) and competitive (K(i) = 0.66 microM) 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.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Voriconazole Cytochrome P450 2C19 Protein Humans UnknownSubstrateInhibitorDetails Voriconazole Cytochrome P450 3A4 Protein Humans UnknownSubstrateInhibitorDetails Voriconazole Cytochrome P450 3A5 Protein Humans UnknownSubstrateInhibitorDetails Voriconazole Cytochrome P450 3A7 Protein Humans UnknownSubstrateInhibitorDetails - Binding Properties
Drug Target Property Measurement pH Temperature (°C) Voriconazole Cytochrome P450 2C19 IC 50 (nM) 5250 N/A N/A Details Voriconazole Cytochrome P450 2C19 IC 50 (nM) 8700 N/A N/A Details Voriconazole Cytochrome P450 2C19 Ki (nM) 5100 N/A N/A Details Voriconazole Cytochrome P450 2C9 IC 50 (nM) 3620 N/A N/A Details Voriconazole Cytochrome P450 2C9 IC 50 (nM) 8400 N/A N/A Details Voriconazole Cytochrome P450 2C9 Ki (nM) 2800 N/A N/A Details - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your software1,2-BenzodiazepineVoriconazole The serum concentration of 1,2-Benzodiazepine can be increased when it is combined with Voriconazole. AcenocoumarolVoriconazole Voriconazole may increase the anticoagulant activities of Acenocoumarol. AlclometasoneVoriconazole The serum concentration of Alclometasone can be increased when it is combined with Voriconazole. AmcinonideVoriconazole The serum concentration of Amcinonide can be increased when it is combined with Voriconazole. AxitinibAcenocoumarol The metabolism of Axitinib can be decreased when combined with Acenocoumarol.