| Biotransformation of prasugrel, a novel thienopyridine antiplatelet agent, to the pharmacologically active metabolite. | |
| | |
MedLine Citation:
|
PMID: 20228231 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
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. |
| | |
Authors:
|
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 |
Affiliation:
|
Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-Ku, Tokyo, 140-8710, Japan. hagihara.katsunobu.fc@daiichisankyo.co.jp |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Biotransformation
/
physiology* Humans Nitrobenzoates / metabolism, pharmacology Piperazines / metabolism, pharmacology* Platelet Aggregation Inhibitors / metabolism, pharmacology* Pyridines / metabolism, pharmacology Sulfhydryl Compounds / metabolism, pharmacology Thiophenes / metabolism, pharmacology* |
| Chemical | |
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 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Differential effects of neuromuscular electrical stimulation parameters on submental motor-evoked po...
Next Document: A comparison of whole genome gene expression profiles of HepaRG cells and HepG2 cells to primary hum...