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.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.035956.
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ABBREVIATIONS:
- 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
- LC
- liquid chromatography
- MS
- mass spectrometry
- HPLC
- high-performance liquid chromatography
- AUC0–2 h
- area under the plasma concentration-time curve up to 2 h
- MS/MS
- tandem mass spectrometry.
- Received August 18, 2010.
- Accepted December 23, 2010.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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