ArticleDrug metabolism and disposition: the biological fate of chemicals2008
Role of flavin-containing monooxygenase in oxidative metabolism of voriconazole by human liver microsomes.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 89 citations in OpenAlex.
- Dose-Dependent Bioavailability and CYP3A Inhibition Contribute to Non-Linear Pharmacokinetics of Voriconazole.Clinical pharmacokinetics · 2016Trial
- A physiologically based pharmacokinetic model for voriconazole disposition predicts intestinal first-pass metabolism in children.Clinical pharmacokinetics · 2014Trial
- Steady-state pharmacokinetics of oral voriconazole and its primary metabolite, N-oxide voriconazole, pre- and post-autologous peripheral stem cell transplantation.Antimicrobial agents and chemotherapy · 2013Trial
- Induction of CYP2C19 and CYP3A activity following repeated administration of efavirenz in healthy volunteers.Clinical pharmacology and therapeutics · 2012Trial
- Assessing the Influence of CYP3A4 Inhibitors on Voriconazole Exposure across CYP2C19 Genotypes: A Physiologically Based Pharmacokinetic Model Analysis.Clinical pharmacokinetics · 2026Article
- Flavin-dependent monooxygenases as versatile biocatalysts in biomanufacturing: mechanisms, engineering, and applications.Biotechnology for biofuels and bioproducts · 2026Review
- Ultrastructural and Immunohistochemical Study on the Nephrotoxicity Following Intravitreal Administration of the Antifungal Agents Voriconazole and Micafungin in New Zealand White Rabbits.International journal of molecular sciences · 2025Article
- Pharmacogenetics of steady-state metabolism, pharmacokinetics, and adverse effects of voriconazole in healthy participants.Drug metabolism and disposition: the biological fate of chemicals · 2025Article
- Drug Metabolism and Pharmacokinetics of Oxazolo[4,5-Pharmaceutics · 2025Article
- Electrochemical Simulation of Phase I Hepatic Metabolism of Voriconazole Using a Screen-Printed Iron(II) Phthalocyanine Electrode.Pharmaceutics · 2023Article
- CYP3A and CYP2C19 Activity Determined by Microdosed Probe Drugs Accurately Predict Voriconazole Clearance in Healthy Adults.Clinical pharmacokinetics · 2023Article
- Development of a New Method for Simultaneous Quantitation of Plasma Concentrations of Voriconazole and VoriconazoleYonago acta medica · 2023Article
- Pharmacokinetic interaction of voriconazole and clarithromycin in Pakistani healthy male volunteers: a single dose, randomized, crossover, open-label study.Frontiers in pharmacology · 2023Article
- Roles of selected non-P450 human oxidoreductase enzymes in protective and toxic effects of chemicals: review and compilation of reactions.Archives of toxicology · 2022Review
- Development of Physiology Based Pharmacokinetic Model to Predict the Drug Interactions of Voriconazole and Venetoclax.Pharmaceutical research · 2022Article
- Impact of polymorphisms of pharmacokinetics-related genes and the inflammatory response on the metabolism of voriconazole.Pharmacology research & perspectives · 2022Article
- Towards the Elucidation of the Pharmacokinetics of Voriconazole: A Quantitative Characterization of Its Metabolism.Pharmaceutics · 2022Article
- Concomitant Treatment with Voriconazole and Flucloxacillin: A Combination to Avoid.Antibiotics (Basel, Switzerland) · 2021Article
- Evaluation of Voriconazole CYP2C19 Phenotype-Guided Dose Adjustments by Physiologically Based Pharmacokinetic Modeling.Clinical pharmacokinetics · 2021Article
- Application of a Physiologically Based Pharmacokinetic Model to Characterize Time-dependent Metabolism of Voriconazole in Children and Support Dose Optimization.Frontiers in pharmacology · 2021Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Voriconazole is a potent second-generation triazole antifungal agent with broad-spectrum activity against clinically important fungi. It is cleared predominantly via metabolism in all species tested including humans. N-Oxidation of the fluoropyrimidine ring, its hydroxylation, and hydroxylation of the adjacent methyl group are the known pathways of voriconazole oxidative metabolism, with the N-oxide being the major circulating metabolite in human. In vitro studies have shown that CYP2C19, CYP3A4, and to a lesser extent CYP2C9 contribute to the oxidative metabolism of voriconazole. When cytochrome P450 (P450)-specific inhibitors and antibodies were used to evaluate the oxidative metabolism of voriconazole by human liver microsomes, the results suggested that P450-mediated metabolism accounted for approximately 75% of the total oxidative metabolism. The studies presented here provide evidence that the remaining approximately 25% of the metabolic transformations are catalyzed by flavin-containing monooxygenase (FMO). This conclusion was based on the evidence that the NADPH-dependent metabolism of voriconazole was sensitive to heat (45 degrees C for 5 min), a condition known to selectively inactivate FMO without affecting P450 activity. The role of FMO in the metabolic formation of voriconazole N-oxide was confirmed by the use of recombinant FMO enzymes. Kinetic analysis of voriconazole metabolism by FMO1 and FMO3 yielded K(m) values of 3.0 and 3.4 mM and V(max) values of 0.025 and 0.044 pmol/min/pmol, respectively. FMO5 did not metabolize voriconazole effectively. This is the first report of the role of FMO in the oxidative metabolism of voriconazole.
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