title: Contributions of intestine and plasma to the presystemic bioconversion of vicagrel, an acetate of clopidogrel.
abstract: OBJECTIVE
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Mailbox 210, #24 Tongjiaxiang, Nanjing, 210009, Jiangsu, China.
authors.forename: Zhixia
authors.initials: Z
authors.lastname: Qiu
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.forename: Ling
authors.initials: L
authors.lastname: Song
authors.forename: Yang
authors.initials: Y
authors.lastname: Lu
authors.forename: Jing
authors.initials: J
authors.lastname: Jing
authors.forename: Harendra S
authors.initials: HS
authors.lastname: Parekha
authors.forename: Wenchao
authors.initials: W
authors.lastname: Gao
authors.forename: Fengjie
authors.initials: F
authors.lastname: Tian
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Shuangxia
authors.initials: S
authors.lastname: Ren
authors.forename: Xijing
authors.initials: X
authors.lastname: Chen
mesh_terms: D000085:Acetates / Q000378:metabolism*; D000818:Animals; D000077144:Clopidogrel; D004950:Esterases / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D007413:Intestinal Mucosa / Q000378:metabolism*; D008861:Microsomes / Q000378:metabolism; D010648:Phenylacetates / Q000097:blood* / Q000378:metabolism*; D011355:Prodrugs / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013876:Thiophenes / Q000097:blood* / Q000378:metabolism*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism
chemical_list: D000085:Acetates; D010648:Phenylacetates; D011355:Prodrugs; D013876:Thiophenes; C574646:methyl 2-(2-acetoxy-6,7-dihydrothieno(3,2-c)pyridin-5(4H)-yl)-2-(2-chlorophenyl)acetate; C540904:2-oxo-clopidogrel; D000077144:Clopidogrel; D004950:Esterases; D013988:Ticlopidine
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