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

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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.

In vivo and in vitro investigation of the contributions of intestine and plasma to the presystemic bioconversion of vicagrel

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Abbreviations

AM:

Active metabolite

AUC:

Area under the plasma concentration versus time curve

BChE:

Butyrylcholine esterases

CE:

Carboxylesterases

CE1:

Carboxylesterases 1

CE2:

Carboxylesterases 2

Cl in vitro :

In vitro intrinsic clearance

CR:

Clopidogrel resistance

PON:

Paraoxonases

PON1:

Paraoxonases 1

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Acknowledgments and Disclosures

The authors thank the State Key Laboratory of Natural Medicines and Center of Drug Discovery (China Pharmaceutical University) and Chia-Tai Tian Qing Pharmaceutical Co. Ltd (Jiangsu, China) for their generous supply of investigated agents. The study was supported by Jiangsu Province Nanjing City Innovative Graduate Research Program (No.CXLL11_0814) and Jiangsu Province Promotion Foundation for the Key Lab of Drug Metabolism and Pharmacokinetics (No.BM2012012).

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Correspondence to Xijing Chen.

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Qiu, Z., Li, N., Song, L. et al. Contributions of Intestine and Plasma to the Presystemic Bioconversion of Vicagrel, an Acetate of Clopidogrel. Pharm Res 31, 238–251 (2014). https://doi.org/10.1007/s11095-013-1158-5

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  • DOI: https://doi.org/10.1007/s11095-013-1158-5

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