@article {Ghosal510, author = {Anima Ghosal and Yuan Yuan and Wei Tong and Ai-Duen Su and Chunyan Gu and Swapan K. Chowdhury and Narendra S. Kishnani and Kevin B. Alton}, title = {Characterization of Human Liver Enzymes Involved in the Biotransformation of Boceprevir, a Hepatitis C Virus Protease Inhibitor}, volume = {39}, number = {3}, pages = {510--521}, year = {2011}, doi = {10.1124/dmd.110.036996}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {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.}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/39/3/510}, eprint = {https://dmd.aspetjournals.org/content/39/3/510.full.pdf}, journal = {Drug Metabolism and Disposition} }