TY - JOUR T1 - Biotransformation of Prasugrel, a Novel Thienopyridine Antiplatelet Agent, to the Pharmacologically Active Metabolite JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 898 LP - 904 DO - 10.1124/dmd.110.032086 VL - 38 IS - 6 AU - Katsunobu Hagihara AU - Miho Kazui AU - Atsushi Kurihara AU - Haruo Iwabuchi AU - Minoru Ishikawa AU - Hiroyuki Kobayashi AU - Naoki Tanaka AU - Osamu Okazaki AU - Nagy A. Farid AU - Toshihiko Ikeda Y1 - 2010/06/01 UR - http://dmd.aspetjournals.org/content/38/6/898.abstract N2 - Prasugrel, a novel thienopyridine antiplatelet agent, undergoes rapid hydrolysis in vivo to a thiolactone, R-95913, which is further converted to its thiol-containing, pharmacologically active metabolite, R-138727, by oxidation via cytochromes P450 (P450). We trapped a sulfenic acid metabolite as a mixed disulfide with 2-nitro-5-thiobenzoic acid in an incubation mixture containing the thiolactone R-95913, expressed CYP3A4, and NADPH. Further experiments investigated one possible mechanism for the conversion of the sulfenic acid to the active thiol metabolite in vitro. A mixed disulfide form of R-138727 with glutathione was found to be a possible precursor of R-138727 in vitro when glutathione was present. The rate constant for the reduction of the glutathione conjugate of R-138727 to R-138727 was increased by addition of human liver cytosol to the human liver microsomes. Thus, one possible mechanism for the ultimate formation of R-138727 in vitro can be through formation of a sulfenic acid mediated by P450s followed possibly by a glutathione conjugation to a mixed disulfide and reduction of the disulfide to the active metabolite R-138727. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics ER -