title: Identification of human liver cytochrome P450 enzymes involved in biotransformation of vicriviroc, a CCR5 receptor antagonist.
abstract: Vicriviroc (SCH 417690), a CCR5 receptor antagonist, is currently under investigation for the treatment of human immunodeficiency virus infection. The objective of this study was to identify human liver cytochrome P450 enzyme(s) responsible for the metabolism of vicriviroc. Human liver microsomes metabolized vicriviroc via N-oxidation (M2/M3), O-demethylation (M15), N,N-dealkylation (M16), N-dealkylation (M41), and oxidation to a carboxylic acid metabolite (M35b/M37a). Recombinant human CYP3A4 catalyzed the formation of all these metabolites, whereas CYP3A5 catalyzed the formation of M2/M3 and M41. CYP2C9 only catalyzed the formation of M15. There was a high correlation between the rates of formation of M2/M3, M15, and M41, which was determined using 10 human liver microsomal samples and testosterone 6beta-hydroxylation catalyzed by CYP3A4/5 (r > or = 0.91). Ketoconazole and azamulin (inhibitors of CYP3A4) were potent inhibitors of the formation of M2/M3, M15, M41, and M35b/M37a from human liver microsomes. A CYP3A4/5-specific monoclonal antibody (1 microg/microg of protein) inhibited the formation of all metabolites from human liver microsomes by 86 to 100%. The results of this study suggest that formation of the major vicriviroc metabolites in human liver microsomes is primarily mediated via CYP3A4. CYP2C9 and CYP3A5 most likely play a minor role in the biotransformation of this compound. These enzymology data will provide guidance to design clinical studies to address any potential drug-drug interactions.
authors.affiliation: Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA. anima.ghosal@spcorp.com
authors.forename: Anima
authors.initials: A
authors.lastname: Ghosal
authors.forename: Ragu
authors.initials: R
authors.lastname: Ramanathan
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yuan
authors.forename: Neil
authors.initials: N
authors.lastname: Hapangama
authors.forename: Swapan K
authors.initials: SK
authors.lastname: Chowdhury
authors.forename: Narendra S
authors.initials: NS
authors.lastname: Kishnani
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Alton
mesh_terms: D000911:Antibodies, Monoclonal; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001711:Biotransformation; D001952:Bridged-Ring Compounds / Q000494:pharmacology; D065100:CCR5 Receptor Antagonists; D002264:Carboxylic Acids / Q000378:metabolism*; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology / Q000378:metabolism*; D003640:Dealkylation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007155:Immunologic Factors / Q000378:metabolism* / Q000494:pharmacology; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D007654:Ketoconazole / Q000494:pharmacology; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D010084:Oxidation-Reduction; D010879:Piperazines / Q000378:metabolism* / Q000494:pharmacology; D011743:Pyrimidines / Q000378:metabolism* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity; D013739:Testosterone / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology