American Society for Pharmacology and Experimental Therapeutics
Drug metabolism and disposition vol:36 issue:6 pages:1119-1125
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 CYP-specific inhibitors and antibodies were used to evaluate the oxidative metabolism of voriconazole by human liver microsomes (HLM), the results suggested that CYP-mediated metabolism accounted for ~75% of the total oxidative metabolism. The studies presented here provide evidence that the remaining ~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 oC for 5 min), a condition known to selectively inactivate FMO without affecting CYP 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 Km values of 3.0 mM and 3.4 mM and Vmax values of 0.025 pmol/min/pmol 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.