Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Mailbox 210, #24 Tongjiaxiang, Nanjing, 210009, Jiangsu, China.
Pharm Res. 2014 Jan;31(1):238-51. doi: 10.1007/s11095-013-1158-5. Epub 2013 Sep 14.
To investigate the contributions of intestine and plasma to the presystemic bioconversion of vicagrel, and track its subsequent bioconversion to 2-oxo-clopidogrel in vivo and in vitro to rationalize the design of vicagrel, an acetate analogue of clopidogrel.
The concentration-time profiles of 2-oxo-clopidogrel and active metabolite (AM) in presystem and circulation system was determined in the cannulated rats. Also, the rat intestinal S9 and human intestinal microsomes were conducted to examine the formation of 2-oxo-clopidogrel and AM. Meanwhile, the esterases in plasma and intestinal fractions responsible for the bioconversion of vicagrel to 2-oxo-clopidogrel were screened by the esterase inhibition and recombinant esterases.
The intestine was responsible for the formation of 2-oxo-clopidogrel and AM in vivo and in vitro, where carboxylesterases 2 (CE2) contributed greatly to the vicagrel cleavage during absorption. Other related esterases in plasma were paraoxonases (PON), carboxylesterases 1 (CE1) and butyrylcholine esterases (BChE).
The findings rationalized the prodrug design hypothesis that vicagrel could overcome the extensive invalid hydrolysis of clopidogrel by the hepatic CE1 but experience the extensive hydrolysis to 2-oxo-clopidogrel and subsequent oxidation to AM in the intestine. This also supported the theory of improved pharmacological activity through facilitated formation of 2-oxo-clopidogrel, thus warranting much needed future clinical pharmacokinetic studies of vicagrel.
研究肠内和血浆在维卡格雷前体药物生物转化中的作用，并追踪其在体内和体外向 2-氧-氯吡格雷的后续生物转化，以合理化维卡格雷（氯吡格雷的醋酸酯类似物）的设计。
通过在套管大鼠中测定 2-氧-氯吡格雷和活性代谢物（AM）在预系统和循环系统中的浓度-时间曲线，来研究 2-氧-氯吡格雷和 AM 的形成。同时，采用大鼠肠 S9 和人肠微粒体来研究 2-氧-氯吡格雷和 AM 的形成。此外，通过酯酶抑制和重组酯酶筛选负责维卡格雷向 2-氧-氯吡格雷生物转化的血浆和肠部分中的酯酶。
肠内是体内和体外形成 2-氧-氯吡格雷和 AM 的部位，其中羧酸酯酶 2（CE2）在吸收过程中对维卡格雷的裂解起重要作用。血浆中其他相关酯酶有对氧磷酶（PON）、羧酸酯酶 1（CE1）和丁酰胆碱酯酶（BChE）。
这些发现合理化了前药设计假说，即维卡格雷可以克服肝羧酸酯酶 1对氯吡格雷的广泛无效水解，但在肠内经历广泛水解为 2-氧-氯吡格雷，随后氧化为 AM。这也支持了通过促进 2-氧-氯吡格雷形成来提高药理学活性的理论，因此需要对维卡格雷进行未来的临床药代动力学研究。
