TY - JOUR T1 - Identification of Enzymes Responsible for Primary and Sequential Oxygenation Reactions of Capravirine in Human Liver Microsomes JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1798 LP - 1802 DO - 10.1124/dmd.106.011189 VL - 34 IS - 11 AU - Hai-Zhi Bu AU - Ping Zhao AU - Ping Kang AU - William F. Pool AU - Ellen Y. Wu Y1 - 2006/11/01 UR - http://dmd.aspetjournals.org/content/34/11/1798.abstract N2 - Capravirine, a new non-nucleoside reverse transcriptase inhibitor, undergoes extensive oxygenation reactions, including N-oxidation, sulfoxidation, sulfonation, and hydroxylation in humans. Numerous primary (mono-oxygenated) and sequential (di-, tri-, and tetraoxygenated) metabolites of capravirine are formed via the individual or combined oxygenation pathways. In this study, cytochrome P450 enzymes responsible for the primary and sequential oxygenation reactions of capravirine in human liver microsomes were identified at the specific pathway level. The total oxygenation of capravirine is mediated predominantly (>90%) by CYP3A4 and marginally (<10%) by CYP2C8, 2C9, and 2C19 in humans. Specifically, each of the two major mono-oxygenated metabolites C23 (sulfoxide) and C26 (N-oxide), is mediated predominantly (>90%) by CYP3A4 and slightly (<10%) by CYP2C8, the minor tertiary hydroxylated metabolite C19 by CYP3A4, 2C8, and 2C19, and the minor primary hydroxylated metabolite C20 by CYP3A4, 2C8, and 2C9. However, all sequential oxygenation reactions are mediated exclusively by CYP3A4. Due to their relatively insignificant contributions of C19 and C20 to total capravirine metabolism, no attempt was made to determine relative contributions of cytochrome P450 enzymes to the formation of the two minor metabolites. The American Society for Pharmacology and Experimental Therapeutics ER -