The Intestine As an Important Contributor to Prasugrel Active Metabolite Formation In Vivo
The Intestine As an Important Contributor to Prasugrel Active Metabolite Formation In Vivo
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DOI：
10.1124/dmd.110.035956
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发表时间：
2011-04-01
影响因子：
3.9
通讯作者：
Kurihara, Atsushi
中科院分区：
文献类型：
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作者：
Hagihara, Katsunobu;Kazui, Miho;Kurihara, Atsushi
Prasugrel[2-acetoxy-5-(alpha-cyclopropylcarbonyl-2-fluorobenzyl)-4，5，6，7-tetrahydrothieno[3，2-c]pyridine]，是一种硫代吡啶类抗血小板药物，在体内快速水解为硫代内酯中间体2-[2-oxo-6，7-dihydrothieno[3，2-c]pyridin-5(4H)-yl]-1-cyclopropyl-2-(2-fluorophenyl)ethanone(R-95913)，后者进一步转化为具有药理活性的代谢物，2-[1-2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-mercapto-3-piperidinylidene醋酸(R-138727)，通过细胞色素P450氧化。在这项研究中，我们研究了门静脉和肝静脉插管犬十二指肠内注射普拉格雷(1 mg/kg)后，肠道和肝脏对R-95913和R-138727形成的贡献。R-95913在门静脉、肝静脉和体静脉的血药浓度-时间曲线下面积分别为525、32和17 ng。H/ml，R-138727分别为564、529和495 ng。H/ml。剂量的普拉格雷在肠道中被吸收，然后分别以93%和13%的比例转化为R-95913和R-138727。在肝脏中，23%的R-95913通过肠道转化为R-138727。总之，这是第一个直接证明普拉格雷在肠道中转化为R-138727的转化率与狗肝脏中转化率相当的报道。
Prasugrel [2-acetoxy-5-(alpha-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.