Contributions of intestine and plasma to the presystemic bioconversion of Vicagrel, an acetate of clopidogrel

Qiu, Zhixia, Li, Ning, Song, Ling, Lu, Yang, Jing, Jing, Parekha, Harendra S., Gao, Wenchao, Tian, Fengjie, Wang, Xin, Ren, Shuangxia and Chen, Xijing (2013) Contributions of intestine and plasma to the presystemic bioconversion of Vicagrel, an acetate of clopidogrel. Pharmaceutical Research, 31 1: 238-251. doi:10.1007/s11095-013-1158-5

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Author Qiu, Zhixia
Li, Ning
Song, Ling
Lu, Yang
Jing, Jing
Parekha, Harendra S.
Gao, Wenchao
Tian, Fengjie
Wang, Xin
Ren, Shuangxia
Chen, Xijing
Title Contributions of intestine and plasma to the presystemic bioconversion of Vicagrel, an acetate of clopidogrel
Journal name Pharmaceutical Research   Check publisher's open access policy
ISSN 0724-8741
1573-904X
Publication date 2013-09-14
Year available 2013
Sub-type Article (original research)
DOI 10.1007/s11095-013-1158-5
Open Access Status Not Open Access
Volume 31
Issue 1
Start page 238
End page 251
Total pages 14
Place of publication New York, NY, United States
Publisher Springer New York
Language eng
Formatted abstract
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.
Keyword 2-Oxo-clopidogrel
Esterases
Presystemic hydrolysis
Vicagrel
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published online: 14 September 2013

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Pharmacy Publications
 
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Created: Mon, 28 Oct 2013, 21:49:15 EST by Harendra Parekh on behalf of School of Pharmacy