PT - JOURNAL ARTICLE AU - Anima Ghosal AU - Yuan Yuan AU - Wei Tong AU - Ai-Duen Su AU - Chunyan Gu AU - Swapan K. Chowdhury AU - Narendra S. Kishnani AU - Kevin B. Alton TI - Characterization of Human Liver Enzymes Involved in the Biotransformation of Boceprevir, a Hepatitis C Virus Protease Inhibitor AID - 10.1124/dmd.110.036996 DP - 2011 Mar 01 TA - Drug Metabolism and Disposition PG - 510--521 VI - 39 IP - 3 4099 - http://dmd.aspetjournals.org/content/39/3/510.short 4100 - http://dmd.aspetjournals.org/content/39/3/510.full SO - Drug Metab Dispos2011 Mar 01; 39 AB - Boceprevir (SCH 503034), a protease inhibitor, is under clinical development for the treatment of human hepatitis C virus infections. In human liver microsomes, formation of oxidative metabolites after incubations with [14C]boceprevir was catalyzed by CYP3A4 and CYP3A5. In addition, the highest turnover was observed in recombinant CYP3A4 and CYP3A5. After a single radiolabeled dose to human, boceprevir was subjected to two distinct pathways, namely cytochrome P450-mediated oxidation and ketone reduction. Therefore, attempts were made to identify the enzymes responsible for the formation of carbonyl-reduced metabolites. Human liver S9 and cytosol converted ∼28 and ∼68% of boceprevir to M28, respectively, in the presence of an NADPH-generating system. Screening of boceprevir with recombinant human aldo-keto reductases (AKRs) revealed that AKR1C2 and AKR1C3 exhibited catalytic activity with respect to the formation of M+2 metabolites (M28 and M31). The formation of M28 was inhibited by 100 μM flufenamic acid (80.3%), 200 μM mefenamic acid (83.7%), and 100 μM phenolphthalein (86.1%), known inhibitors of AKRs, suggesting its formation through carbonyl reduction pathway. Formation of M28 was also inhibited by 100 μM diazepam (75.1%), 1 mM ibuprofen (70%), and 200 μM diflunisal (89.4%). These data demonstrated that CYP3A4 and CYP3A5 are primarily responsible for the formation of oxidative metabolites and the formation of M28 and M31, the keto-reduced metabolites, are most likely mediated by AKR1C2 and AKR1C3. Because the biotransformation and clearance of boceprevir involves two different enzymatic pathways, boceprevir is less likely to be a victim of significant drug-drug interaction with concomitant medication affecting either of these pathways.