Ghosal Anima, Ramanathan Ragu, Yuan Yuan, Hapangama Neil, Chowdhury Swapan K, Kishnani Narendra S, Alton Kevin B
Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA.
Drug Metab Dispos. 2007 Dec;35(12):2186-95. doi: 10.1124/dmd.107.017517. Epub 2007 Sep 7.
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.
维克立罗（SCH 417690）是一种CCR5受体拮抗剂，目前正在进行治疗人类免疫缺陷病毒感染的研究。本研究的目的是确定负责维克立罗代谢的人肝细胞色素P450酶。人肝微粒体通过N-氧化（M2/M3）、O-去甲基化（M15）、N，N-脱烷基化（M16）、N-脱烷基化（M41）以及氧化生成羧酸代谢物（M35b/M37a）来代谢维克立罗。重组人CYP3A4催化所有这些代谢物的形成，而CYP3A5催化M2/M3和M41的形成。CYP2C9仅催化M15的形成。使用10个人肝微粒体样品和由CYP3A4/5催化的睾酮6β-羟基化测定，M2/M3、M15和M41的形成速率之间存在高度相关性（r≥0.91）。酮康唑和阿扎木林（CYP3A4抑制剂）是从人肝微粒体中形成M2/M3、M15、M41和M35b/M37a的有效抑制剂。一种CYP3A4/5特异性单克隆抗体（1μg/μg蛋白质）将人肝微粒体中所有代谢物的形成抑制了86%至100%。本研究结果表明，人肝微粒体中主要维克立罗代谢物的形成主要通过CYP3A4介导。CYP2C9和CYP3A5在该化合物的生物转化中最可能起次要作用。这些酶学数据将为设计临床研究以解决任何潜在的药物相互作用提供指导。
