TY - JOUR T1 - Biosynthesis and Identification of Metabolites of Maraviroc and Their Use in Experiments to Delineate the Relative Contributions of Cytochrome P4503A4 versus 3A5 JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 493 LP - 502 DO - 10.1124/dmd.117.079855 VL - 46 IS - 5 AU - Elaine Tseng AU - Gwendolyn D. Fate AU - Gregory S. Walker AU - Theunis C. Goosen AU - R. Scott Obach Y1 - 2018/05/01 UR - http://dmd.aspetjournals.org/content/46/5/493.abstract N2 - Maraviroc (MVC) is a CCR5 coreceptor antagonist indicated in combination with other antiretroviral agents for the treatment of CCR5-tropic human immunodefinciency virus-1 infection. In this study, the metabolism of MVC was investigated in human liver microsomes to delineate the relative roles of CYP3A4 and CYP3A5. MVC is metabolized to five hydroxylated metabolites, all of which were biosynthesized and identified using mass and NMR spectroscopy. The sites of metabolism were the 2- and 3-positions of the 4,4-difluorocyclohexyl moiety and the methyl of the triazole moiety. Absolute configurations were ultimately ascertained by comparison to authentic standards. The biosynthesized metabolites were used for quantitative in vitro experiments in liver microsomes using cyp3cide, a selective inactivator of CYP3A4. (1S,2S)-2-OH-MVC was the main metabolite representing approximately half of the total metabolism, and CYP3A5 contributed approximately 40% to that pathway in microsomes from CYP3A5*1/*1 donors. The other four metabolites were almost exclusively metabolized by CYP3A4. (1S,2S)-2-hydroxylation also correlated to T-5 N-oxidation, a CYP3A5-specific activity. These data are consistent with clinical pharmacokinetic data wherein CYP3A5 extensive metabolizer subjects showed a modestly lower exposure to MVC. ER -