Document Detail

Biotransformation of prasugrel, a novel thienopyridine antiplatelet agent, to the pharmacologically active metabolite.
MedLine Citation:
PMID:  20228231     Owner:  NLM     Status:  MEDLINE    
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.
Katsunobu Hagihara; Miho Kazui; Atsushi Kurihara; Haruo Iwabuchi; Minoru Ishikawa; Hiroyuki Kobayashi; Naoki Tanaka; Osamu Okazaki; Nagy A Farid; Toshihiko Ikeda
Publication Detail:
Type:  Journal Article     Date:  2010-03-12
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  38     ISSN:  1521-009X     ISO Abbreviation:  Drug Metab. Dispos.     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-05-14     Completed Date:  2010-08-20     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  United States    
Other Details:
Languages:  eng     Pagination:  898-904     Citation Subset:  IM    
Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-Ku, Tokyo, 140-8710, Japan.
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MeSH Terms
Biotransformation / physiology*
Nitrobenzoates / metabolism,  pharmacology
Piperazines / metabolism,  pharmacology*
Platelet Aggregation Inhibitors / metabolism,  pharmacology*
Pyridines / metabolism,  pharmacology
Sulfhydryl Compounds / metabolism,  pharmacology
Thiophenes / metabolism,  pharmacology*
Reg. No./Substance:
0/Nitrobenzoates; 0/Piperazines; 0/Platelet Aggregation Inhibitors; 0/Pyridines; 0/R-138727; 0/Sulfhydryl Compounds; 0/Thiophenes; 0/prasugrel; 0/thienopyridine; 15139-21-6/thionitrobenzoic acid

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