The Disposition of Prasugrel, a Novel Thienopyridine, in Humans

Nagy A. Farid; Richard L. Smith; Todd A. Gillespie; T. James Rash; Patrick E. Blair; Atsushi Kurihara; Mark J. Goldberg

doi:10.1124/dmd.106.014522

Abstract

Prasugrel, a prodrug, is a novel and potent inhibitor of platelet aggregation in vivo. The metabolism of prasugrel and the elimination and pharmacokinetics of its active metabolite, 2-[1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-mercapto-3-piperidinylidene]acetic acid (R-138727), three inactive metabolites, and radioactivity were determined in five healthy male subjects after a single 15-mg (100 μCi) p.o. dose of [¹⁴C]prasugrel. Prasugrel was rapidly absorbed, and maximum plasma concentrations of radioactivity and R-138727 were achieved in 30 min, indicating rapid formation of R-138727. Prasugrel was extensively metabolized in humans, first by hydrolysis to a thiolactone, followed by ring opening to form R-138727, which was further metabolized by S-methylation and conjugation with cysteine. Total radioactivity was higher in plasma than in blood, suggesting limited penetration of prasugrel metabolites into red blood cells. Approximately 70% of the dose was excreted in the urine and 25% in the feces.

Footnotes

A portion of this work was presented at the 13th North American ISSX/20th JSSX Meeting, Maui, Hawaii, 2005 and was published in an abstract form in Drug Metab Rev37 (Suppl 2):86.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.106.014522.
ABBREVIATIONS: prasugrel, (±)-2-[2-acetyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]-1-cyclopropyl-2-(2-fluorophenyl)ethanone; R-138727, 2-[1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-mercapto-3-piperidinylidene]acetic acid; R-95913, 2-[2-oxo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]-1-cyclopropyl-2-(2-fluorophenyl)ethanone; R-106583, 2-[1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-(methylthio)-3-piperidylidene]acetic acid; R-119251, (Z)-4-[(R)-2-amino-2-carboxyethyldisulfanyl]-3-carboxymethylidene-1-(α-cyclopropylcarbonyl-2-fluorobenzyl)piperidene; R-118443, 4-[(R)-2-amino-2-carboxyethyldisulfanyl]-3-carboxymethyl-1-(α-cyclopropylcarbonyl-2-fluorobenzyl)-1,2,5,6-tetrahydropyridine; R-100932, 2-[1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-(methylthio)-1,2,5,6-tetrahydropyridin-3-yl]acetic acid; HPLC, high-performance liquid chromatography; LC/MS/MS, liquid chromatography/tandem mass spectrometry; LSC, liquid scintillation counting; AUC, area under the plasma concentration versus time curve; MS, mass spectrometry; DTT, dithiothreitol.
- Received January 5, 2007.
- Accepted March 29, 2007.