Abstract：
This study aimed to determine changes in the hydrolysis of vicagrel, a substrate drug of arylacetamide deacetylase (Aadac) and carboxylesterase 2 (Ces2), in P-glycoprotein (P-gp)-deficient or P-gp-inhibited mice and to elucidate the mechanisms involved.Male wild-type (WT) and P-gp knock-out (KO) mice were used to investigate the systemic exposure of vicagrel thiol active metabolite H4 and platelet response to vicagrel, and the mRNA and protein expression levels of intestinal Aadac and Ces2. Moreover, WT mice were administered vicagrel alone or in combination with elacridar (a potent P-gp inhibitor) to determine drug-drug interactions.Compared with WT mice, P-gp KO mice exhibited significant increases in the systemic exposure of H4, the protein expression levels of intestinal Aadac and Ces2, and inhibition of ADP-induced platelet aggregation by vicagrel. Further, the H4 exposure was positively correlated with intestinal Aadac protein expression levels but did not vary with short-term inhibition of P-gp efflux activity by elacridar.P-gp-deficient mice, rather than elacridar-treated mice, exhibited significant upregulation of intestinal Aadac and Ces2 and thus, enhanced metabolic activation of and platelet response to vicagrel, suggesting that the metabolic activation of vicagrel may vary with P-gp deficiency, not P-gp inhibition, in mice.
摘要：
这项研究的目的是确定在水解的变化，芳基乙酰胺脱乙酰酶（Aadac）和羧酸酯酶2（Ces2）的底物药物，在P-糖蛋白（P-gp）缺陷或P-gp抑制的小鼠中，并阐明所涉及的机制。雄性野生型（WT）和P-gp敲除（KO）小鼠用于研究维格雷硫醇活性代谢产物H4的全身暴露和血小板对维格雷的反应。以及肠道Aadac和Ces2的mRNA和蛋白表达水平。此外，WT小鼠单独或与elacridar（一种有效的P-gp抑制剂）联合施用维格雷钠，以确定药物-药物相互作用。与WT小鼠相比，P-gpKO小鼠表现出H4的全身暴露，肠道Aadac和Ces2的蛋白表达水平显着增加，并通过维格雷抑制ADP诱导的血小板聚集。然而,H4暴露与肠道Aadac蛋白表达水平呈正相关，但不随elacridar对P-gp外排活性的短期抑制而变化。P-gp缺陷小鼠,而不是用elacridar治疗的小鼠，表现出肠Aadac和Ces2的显着上调，因此，增强的代谢激活和血小板反应，提示维格雷的代谢激活可能随P-gp缺乏而变化，不是P-gp抑制，在老鼠身上。
