TY - JOUR T1 - Atazanavir metabolism according to CYP3A5 status: An in vitro – in vivo assessment JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.110.036178 SP - dmd.110.036178 AU - Michael F Wempe AU - Peter L Anderson Y1 - 2010/12/09 UR - http://dmd.aspetjournals.org/content/early/2010/12/09/dmd.110.036178.abstract N2 - The current study was a follow up to an in vivo study where atazanavir oral clearance was shown to be dependent on genetically-determined CYP3A5 expression status, but only in non-African Americans (Anderson et al, 2009). This study aimed to identify atazanavir metabolites generated by CYP3A5 and to evaluate this metabolite pattern in the African American versus non-African American CYP3A5 expressors from the previous study. First, the in vitro metabolism of atazanavir was evaluated using human liver microsomes (HLM), CYP3A4 and CYP3A5 isoforms. Second, the metabolite pattern generated by CYP3A5 was evaluated in human plasma samples from the previous study. Atazanavir metabolites were analyzed using LC-MS/MS methods. Metabolite AUCs were normalized to atazanavir AUC to generate an AUC ratio. Sixteen metabolites were observed in HLM incubations representing five 'Phase I' biotransformation pathways. Mono-oxidation products (M1 and M2) were formed by CYP3A5 at a faster rate than CYP3A4 by 32- and 2.6-fold, respectively. This finding was replicated in HLMs from a genetically-determined CYP3A5 expressor versus non-expressor. In the in vivo samples, the M1 and M2 AUC ratios were about 2-fold higher in CYP3A5 expressors versus non-expressors (P<0.05) and the difference was similar in African-Americans and non-African Americans. Thus, CYP3A5 produced a unique metabolite 'signature' for atazanavir in vitro and in vivo, independent of race. Therefore, other pharmacological factors are likely to explain the apparent lack of effect of genetically-determined CYP3A5 expressor status on atazanavir oral clearance in African Americans from the previous study. ER -