TY - JOUR T1 - In Vitro Hepatic Metabolism Explains Higher Clearance of Voriconazole in Children versus Adults: Role of CYP2C19 and FMO3 JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.109.029769 SP - dmd.109.029769 AU - Souzan B. Yanni AU - Pieter P. Annaert AU - Patrick Augustijns AU - Joseph G. Ibrahim AU - Daniel K. Benjamin AU - Dhiren R. Thakker Y1 - 2009/01/01 UR - http://dmd.aspetjournals.org/content/early/2009/10/19/dmd.109.029769.abstract N2 - Voriconazole is a broad spectrum antifungal agent for treating life threatening fungal infections. Its clearance is approximately three-fold higher in children compared to adults. Voriconazole is cleared predominantly via hepatic metabolism in adults, mainly by CYP3A4, CYP2C19, and flavin-containing monooxygenase 3 (FMO3). In vitro metabolism of voriconazole by liver microsomes prepared from pediatric and adult tissues (n=6/group) mirrored the in vivo clearance differences in children versus adults, and showed that the oxidative metabolism was significantly faster in children compared to adults as indicated by the in vitro half-life (T ½) of 33.8 ± 15.3 versus 72.6 ± 23.7 min, respectively. The Km for voriconazole metabolism to N-oxide, the major metabolite formed in humans, by liver microsomes from children and adults was similar (11.0 ± 5.2 μM versus 9.3 ± 3.6 μM, respectively). In contrast, apparent Vmax was approximately 3-fold higher in children compared to adults (120.5 ± 99.9 versus 40.0 ± 13.9 pmol/min/mg). The calculated in vivo clearance from in vitro data was found to be approximately 80% of the observed plasma clearance values in both populations. Metabolism studies in which CYP3A4, CYP2C19, or FMO was selectively inhibited provided evidence that contribution of CYP2C19 and FMO toward voriconazole N-oxidation was much greater in children than in adults, whereas CYP3A4 played a larger role in adults. While expression of CYP2C19 and FMO3 is not significantly different in children versus adults, these enzymes appear to contribute to higher metabolic clearance of voriconazole in children versus adults.The American Society for Pharmacology and Experimental Therapeutics ER -