Abstract
Vicagrel, a structural analog of clopidogrel, is now being developed as a thienopyridine antiplatelet agent in a phase II clinical trial in China. Some studies have shown that vicagrel undergoes complete first-pass metabolism in human intestine, generating the hydrolytic metabolite 2-oxo-clopidogrel via carboxylesterase-2 (CES2) and subsequently the active metabolite H4 via CYP450s. This study aimed to identify hydrolases other than CES2 that are involved in the bioactivation of vicagrel in human intestine. This study is the first to determine that human arylacetamide deacetylase (AADAC) is involved in 2-oxo-clopidogrel production from vicagrel in human intestine. In vitro hydrolytic kinetics were determined in human intestine microsomes and recombinant human CES and AADAC. The calculated contribution of CES2 and AADAC to vicagrel hydrolysis was 44.2 and 53.1% in human intestine, respectively. The AADAC-selective inhibitors vinblastine and eserine effectively inhibited vicagrel hydrolysis in vitro. In addition to CES2, human intestine AADAC was involved in vicagrel hydrolytic activation before it entered systemic circulation. In addition, simvastatin efficiently inhibited the production of both 2-oxo-clopidogrel and active H4; further clinical trials are needed to determine whether the hydrolytic activation of vicagrel is influenced by coadministration with simvastatin. This study deepens the understanding of the bioactivation and metabolism properties of vicagrel in humans, which can help further understand the bioactivation mechanism of vicagrel and the variations in the treatment responses to vicagrel and clopidogrel.
Highlights
The thiophenopyridine antiplatelet agent clopidogrel is a second-generation platelet ADP receptor antagonist that has become a routine drug for antiplatelet therapy after coronary intervention
The hydrolytic metabolite 2oxo-clopidogrel that is absorbed into the body is metabolized to the endo form by paraoxonase in plasma (Dansette et al, 2012; Qiu et al, 2016), used to produce the active metabolite H4 by CYP450, or hydrolyzed to carboxylic acid metabolites by liver esterases (Zhu et al, 2013)
For kinetic analyses of vicagrel hydrolase activity, probe substrates, including fenofibrate, procaine, and phenacetin were used as markers of carboxylesterase 1 (CES1), CES2, and arylacetamide deacetylase (AADAC), respectively, to confirm the hydrolase activities of these enzyme sources
Summary
The thiophenopyridine antiplatelet agent clopidogrel is a second-generation platelet ADP receptor antagonist that has become a routine drug for antiplatelet therapy after coronary intervention. H4 (Figure 1) is the main active ingredient for clopidogrel, that prevents platelet. CYP2C19 gene polymorphism affects the treatment response to clopidogrel. Some patients showed low or even no response to clopidogrel treatment (Barragan et al, 2003; Gurbel et al, 2005), which is called “clopidogrel resistance.”. In China, the major CYP2C19 genotypes are ∗1/∗1 and ∗1/∗2, each of which comprise approximately 43% of the population (Myrand et al, 2008). 16% of the Chinese population carry two CYP2C19-deficient genes, and become the poor metabolizers of clopidogrel (Kelly et al, 2012). Studies have shown that the probability of cardiovascular adverse events in patients with two CYP2C19-deficient genes (∗ 2, ∗ 3, ∗ 4, or ∗ 5) was 3.58 times higher than in patients without mutated genes (Simon et al, 2009)
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