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Vol. 31, Issue 5, 540-547, May 2003
Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer
Global Research and Development, Sandwich, Kent, United Kingdom
Voriconazole is a triazole antifungal agent with potent activity
against a broad spectrum of clinically significant pathogens. In vivo
and in vitro studies have demonstrated that voriconazole is extensively
metabolized, with the major circulating metabolite resulting from
N-oxidation. In the present study, we report on the
human cytochrome P450 enzymes responsible for the generation of this
metabolite. In human liver microsomes voriconazole
N-oxidation exhibited biphasic kinetics with
Km1 of 8.1 µM, and
Km2 of 835 µM. Studies at 2500 µM
voriconazole identified CYP3A4 as the low-affinity component, with
activity correlating strongly with CYP3A4 activity in a bank of human
liver microsomes (r = 0.90) and inhibited by ketoconazole. At 25 µM, voriconazole N-oxidation
showed strong correlation with CYP2C19 and CYP3A4 activity
(r = 0.77 and 0.74, respectively) and was inhibited
by both sulfaphenazole and ketoconazole. Incubations with recombinant
enzymes suggested both CYP2C9 and CYP2C19 as high-affinity enzymes
(Km values of 20 and 3.5 µM, respectively). Further studies used chemical inhibitors in human liver
microsomes prepared from individual donors, including two CYP2C19 poor
metabolizers. No inhibition was observed with sulfaphenazole, indicating a minor role for CYP2C9 in human liver, but inhibition by
ketoconazole was most potent in the CYP2C19 poor metabolizer livers,
suggesting an increased role for CYP3A4 in individuals lacking CYP2C19.
These data indicate that voriconazole is a substrate for CYP2C9,
CYP2C19, and CYP3A4, with CYP2C9 involvement being minimal in human
liver microsomes. Genotype status for CYP2C19 and/or coadministration
of drugs that modulate CYP2C19 or CYP3A4 activities could effect
voriconazole plasma levels.
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