RT Journal Article
SR Electronic
T1 Biotransformation of Prasugrel, a Novel Thienopyridine Antiplatelet Agent, to the Pharmacologically Active Metabolite
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 898
OP 904
DO 10.1124/dmd.110.032086
VO 38
IS 6
A1 Katsunobu Hagihara
A1 Miho Kazui
A1 Atsushi Kurihara
A1 Haruo Iwabuchi
A1 Minoru Ishikawa
A1 Hiroyuki Kobayashi
A1 Naoki Tanaka
A1 Osamu Okazaki
A1 Nagy A. Farid
A1 Toshihiko Ikeda
YR 2010
UL http://dmd.aspetjournals.org/content/38/6/898.abstract
AB 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