title: The intestine as an important contributor to prasugrel active metabolite formation in vivo.
abstract: Prasugrel [2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine], a thienopyridine antiplatelet agent, undergoes rapid hydrolysis in vivo to a thiolactone intermediate, 2-[2-oxo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]-1-cyclopropyl-2-(2-fluorophenyl)ethanone (R-95913), which is further converted to a pharmacologically active metabolite, 2-[1-2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-mercapto-3-piperidinylidene acetic acid (R-138727), by oxidation via cytochromes P450. In this study, we investigated how much the intestine and liver contribute to the formation of R-95913 and R-138727 after intraduodenal administration of prasugrel (1 mg/kg) to portal vein- and hepatic vein-cannulated dogs. The areas under the plasma concentration-time curve up to 2 h of R-95913 in the portal, hepatic, and systemic veins were 525, 32, and 17 ng · h/ml, respectively, and those of R-138727 were 564, 529, and 495 ng · h/ml, respectively. The dose of prasugrel was absorbed and then converted to R-95913 and R-138727 by 93 and 13%, respectively, in the intestine. In the liver, 23% of the R-95913, which passed through the intestine, was converted to R-138727. In conclusion, this is the first report to directly demonstrate that the conversion of prasugrel to R-138727 in the intestine is comparable to that converted in the liver of dogs.
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-Ku, Tokyo, Japan. hagihara.katsunobu.fc@daiichisankyo.co.jp
authors.forename: Katsunobu
authors.initials: K
authors.lastname: Hagihara
authors.forename: Miho
authors.initials: M
authors.lastname: Kazui
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ikenaga
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Nanba
authors.forename: Kiichi
authors.initials: K
authors.lastname: Fusegawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Izumi
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Ikeda
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kurihara
mesh_terms: D000818:Animals; D019540:Area Under Curve; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004285:Dogs; D006801:Humans; D006868:Hydrolysis; D007413:Intestinal Mucosa / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008861:Microsomes; D008862:Microsomes, Liver; D010084:Oxidation-Reduction; D010879:Piperazines / Q000097:blood / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D010975:Platelet Aggregation Inhibitors / Q000097:blood / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D000068799:Prasugrel Hydrochloride; D013876:Thiophenes / Q000097:blood / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; C510685:R-138727; D013876:Thiophenes; D003577:Cytochrome P-450 Enzyme System; D000068799:Prasugrel Hydrochloride