Arylacetamide Deacetylase Is Involved in Vicagrel Bioactivation in Humans

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.

Impacts of CYP2C19 genetic polymorphisms on bioavailability and effect on platelet adhesion of vicagrel, a novel thienopyridine P2Y12 inhibitor

“…Vicagrel and clopidogrel have pharmacological effects based on the same active thiol metabolite, H4, which is formed through a 2‐step metabolic activation process (Figure 1). 12,23–27 The second step, from 2‐oxo‐clopidogrel to the thiol metabolite, H4, is the same for both vicagrel and clopidogrel. However, for vicagrel, the first step is the rapid and complete hydrolysis of its ester function to form 2‐oxo‐clopidogrel, which is mediated by human carboxylesterase 2 and arylacetamide deacetylase in the gut instead of CYP2C19 in the liver.…”

Enhanced responsiveness of platelets to vicagrel in IL‐10‐deficient mice through STAT3‐dependent up‐regulation of the hydrolase arylacetamide deacetylase in the intestine

“…Li et al, 2018;Shan et al, 2012;Xie et al, 2017). As illustrated in Figure 1, vicagrel undergoes complete hydrolysis in the intestine by AADAC and CES2 to generate its immediate metabolite 2-oxo-clopidogrel (precursor of the active metabolite H4) before it exerts its antiplatelet effect (Jiang et al, 2017;Qiu et al, 2014;Xie et al, 2017). In humans, the relative contribution of AADAC to generating 2-oxo-clopidogrel is roughly 53% (Jiang et al, 2017).…”

“…As a prodrug, vicagrel exerts its potent antiplatelet effect via a two-step metabolic pathway to form its active metabolite H4 as shown in Figure 1. Several drug-metabolizing enzymes are known to be involved in these processes, including AADAC (Jiang et al, 2017) and CES2 (Qiu et al, 2014;Xie et al, 2017) for vicagrel hydrolysis in the intestine, and CYP3A4, CYP2B6, CYP2C19, and CYP2C9 for its second-step oxidation in the liver (Xie et al, 2011(Xie et al, , 2017. To determine whether IL-10 could significantly modulate the expression levels of these genes, we measured the mRNA expression levels of the mouse-specific orthologue genes of human genes…”

“…Limited evidence indicated that as an acetate analogue of clopidogrel, vicagrel is different from clopidogrel in their metabolic activation (Kazui et al, 2010;Xie et al, 2017). For example, Aadac and Ces2 hydrolases in the intestine are recently identified as the most predominant enzymes responsible for the complete hydrolysis of vicagrel to generate 2-oxo-clopidogrel (Jiang et al, 2017;Qiu et al, 2014), whereas hepatic Cyp3a and Cyp2c…”

“…Li et al, 2018;Shan et al, 2012;Xie, Jia, Tai, & Ji, 2017). As illustrated in Figure 1, the metabolic activation of vicagrel is predominantly catalysed by intestinal arylacetamide deacetylase (AADAC) and carboxylesterase (CES) 2 (Jiang, Chen, & Zhong, 2017), rather than hepatic P450 enzymes (Qiu et al, 2014), different from that of clopidogrel (Xie et al, 2017). However, little is known about whether the presence or absence of IL-10 could affect the metabolic activation of and platelet responses to vicagrel despite some clinical findings that elevated plasma IL-10 levels are associated with impaired platelet responses to clopidogrel and also with worse prognosis in patients with coronary heart disease (Heeschen et al, 2003;Osmancik et al, 2012;Shibata et al, 1997;Yip et al, 2007).…”