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

Seongwook Jeong, Phuong D. Nguyen, Zeruesenay Desta

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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 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.

Original languageEnglish
Pages (from-to)541-551
Number of pages11
JournalAntimicrobial Agents and Chemotherapy
Volume53
Issue number2
DOIs
StatePublished - Feb 2009

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Cytochrome P-450 Enzyme System
Cytochrome P-450 CYP3A
Liver Microsomes
Pharmaceutical Preparations
Voriconazole
In Vitro Techniques
Cytochrome P-450 CYP1A2
Cytochrome P-450 CYP2D6
Drug Interactions
Inhibitory Concentration 50
Protein Isoforms
Cytochrome P-450 CYP2C19
Cytochrome P-450 CYP2C9

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Infectious Diseases

Cite this

Comprehensive in vitro analysis of voriconazole inhibition of eight cytochrome P450 (CYP) enzymes : Major effect on CYPs 2B6, 2C9, 2C19, and 3A. / Jeong, Seongwook; Nguyen, Phuong D.; Desta, Zeruesenay.

In: Antimicrobial Agents and Chemotherapy, Vol. 53, No. 2, 02.2009, p. 541-551.

Research output: Contribution to journalArticle

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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 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.",
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