Biotransformation of prasugrel, a novel thienopyridine antiplatelet agent, to the pharmacologically active metabolite.
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.
Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-Ku, Tokyo, 140-8710, Japan. hagihara.katsunobu.fc@daiichisankyo.co.jp
Katsunobu
K
Hagihara
Miho
M
Kazui
Atsushi
A
Kurihara
Haruo
H
Iwabuchi
Minoru
M
Ishikawa
Hiroyuki
H
Kobayashi
Naoki
N
Tanaka
Osamu
O
Okazaki
Nagy A
NA
Farid
Toshihiko
T
Ikeda
D001711:Biotransformation / Q000502:physiology*; D006801:Humans; D009579:Nitrobenzoates / Q000378:metabolism / Q000494:pharmacology; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D000068799:Prasugrel Hydrochloride; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000378:metabolism / Q000494:pharmacology; D013876:Thiophenes / Q000378:metabolism / Q000494:pharmacology*
D009579:Nitrobenzoates; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; C510685:R-138727; D013438:Sulfhydryl Compounds; D013876:Thiophenes; C446540:thienopyridine; C011136:thionitrobenzoic acid; D000068799:Prasugrel Hydrochloride