The Intestine As an Important Contributor to Prasugrel Active Metabolite Formation In Vivo

Abstract

ABSTRACT:Prasugrel [2-acetoxy-5-(␣-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 ⅐ h/ml, respectively, and those of R-138727 were 564, 529, and 495 ng ⅐ 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. IntroductionPrasugrel [2-acetoxy-5-(␣-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine; Effient in the United States and Efient in the European Union], clopidogrel (Plavix/Iscover), and ticlopidine (Ticlid) are thienopyridine antiplatelet agents. Prasugrel is indicated to reduce the rate of thrombotic cardiovascular events and stent thrombosis in patients with acute coronary syndrome who are undergoing percutaneous coronary intervention (Wiviott et al., 2007; Effient package insert, Eli Lilly and Company, Indianapolis, IN). The thienopyridines are prodrugs that are converted in vivo to their pharmacologically active metabolites possessing a thiol group via a corresponding thiolactone metabolite (Farid et al., 2010). In clinical trials, prasugrel achieved a greater and faster antiplatelet effect than clopidogrel (Payne et al., 2007;Wallentin et al., 2008). Such responses to prasugrel are attributed to higher and faster exposure to its active metabolite R-138727 (2-[1-2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-mercapto-3-piperidinylidene acetic acid) than clopidogrel's response (Sugidachi et al., 2007;Ernest et al., 2008). Prasugrel is rapidly hydrolyzed to a thiolactone intermediate R-95913 (2-[2-oxo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]-1-cyclopropyl-2-(2-fluorophenyl)ethanone), mainly by human carboxylesterase 2 during absorption through the gastrointestinal tract (Williams et al., 2008). R-95913 is metabolized to R-138727 by cytochrome P450 isoforms, and the main contributors are CYP3A4 and CYP2B6 (38 -70 and 2-36%, respectively), with smaller contributions by CYP2C9 and CYP2C19 (14 -19 and 8 -11%, respectively) (Rehme...

Arylacetamide Deacetylase is Responsible for Activation of Prasugrel in Human and Dog

“…The results suggested that AADAC is involved in prasugrel hydrolysis in human intestine and liver. The high CL int value in HIMs suggests that a large portion of prasugrel was hydrolyzed in the intestine after oral administration, as previously reported (Hagihara et al, 2011). The K m value by recombinant CES1 in this study (16.7 6 1.9 mM) was similar to that reported in a previous study using purified CES1 (9.3 6 0.8 mM) (Williams et al, 2008).…”

“…In dogs, both CES1 and CES2 are expressed in the liver but not in the intestine (Taketani et al, 2007). Although substrates of CES enzymes are predicted to be unlikely hydrolyzed in the dog intestine, a previous study reported that the dog intestinal S9 fraction showed prasugrel hydrolase activity comparable to the human intestinal S9 fraction (Hagihara et al, 2011). This result made us hypothesize that enzyme(s) other than CES2 are involved in prasugrel hydrolysis.…”

“…It has been believed that prasugrel hydrolysis was catalyzed by CES2 in humans (Williams et al, 2008). High prasugrel hydrolase activity was observed in dog intestine (Hagihara et al, 2011), even though CES2 protein is not expressed in dog intestine (Taketani et al, 2007). This fact implies a possibility that enzyme(s) other than CES enzymes would catalyze prasugrel hydrolysis.…”

“…Because phenacetin hydrolase activity in DIMs (322.5 6 65.1 pmol/min/mg protein at 5 mM phenacetin) was lower than that in HIMs (1927.5 6 67.9 pmol/min/mg protein, data not shown), it was surmised that AADAC expression in dog intestine would be much lower than that in human intestine. Nevertheless, it has been reported that prasugrel is extensively hydrolyzed in the small intestine after oral doses in dogs (Hagihara et al, 2011). This would be due to the high absolute CL int value of prasugrel hydrolysis in DIMs (5.6 6 0.3 ml/min/mg protein).…”

Ontogenic expression of human carboxylesterase-2 and cytochrome P450 3A4 in liver and duodenum: Postnatal surge and organ-dependent regulation

“…4A). In support of this possibility, hydrolysis of the antiplatelet agent prasugrel was comparable between the small intestine and liver in dogs (Hagihara et al, 2011). …”