Contributions of Intestine and Plasma to the Presystemic Bioconversion of Vicagrel, an Acetate of Clopidogrel

Purpose 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. Methods 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. Results 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). Conclusion 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.