Aspirin Attenuates the Bioactivation of and Platelet Response to Vicagrel in Mice
Aspirin Attenuates the Bioactivation of and Platelet Response to Vicagrel in Mice
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DOI：
10.1097/fjc.0000000000000622
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发表时间：
2018-11
影响因子：
3
通讯作者：
Yu-Meng Jia;Tong-Tong Gu-Tong;Jin-Zi Ji;T. Tai;Meng-Ran Zhang;Bei-Bei Huang-Bei;Huan Zhou;Qiong-Yu Mi;Hong-Guang Xie
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文献类型：
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作者：
Yu-Meng Jia;Tong-Tong Gu-Tong;Jin-Zi Ji;T. Tai;Meng-Ran Zhang;Bei-Bei Huang-Bei;Huan Zhou;Qiong-Yu Mi;Hong-Guang Xie
摘要：维卡格雷是氯吡格雷的一种新型醋酸盐类似物，在啮齿类动物中比氯吡格雷具有更强的抗血小板作用。相关证据表明，阿司匹林和维卡格雷是羧酸酯酶2的药物底物。据此推测，合用阿司匹林可减弱维卡格雷的生物活性和血小板反应。为了阐明是否存在如此重要的药物相互作用，测量并比较了单独使用维卡格雷或与阿司匹林联合治疗的小鼠之间维卡格雷活性代谢物 H4 的形成以及维卡格雷对二磷酸腺苷诱导的血小板聚集的抑制作用的差异。采用液相色谱-串联质谱法测定血浆H4浓度，并通过全血血小板聚集评估维卡格雷对血小板聚集的抑制作用。与单独使用维卡格雷（2.5 mg·kg−1）相比，同时使用阿司匹林（5、10或20 mg·kg−1）可显着降低H4的全身暴露，与10 mg·kg−1阿司匹林合用时，小鼠的Cmax和AUC0–∞平均分别降低38%和41%。此外，同时使用阿司匹林（10 mg·kg−1）和维卡格雷（2.5 mg·kg−1）可使维卡格雷对二磷酸腺苷诱导的血小板聚集的抑制作用平均降低 66%。我们得出的结论是，阿司匹林显着减弱小鼠体内维卡格雷活性代谢物 H4 的形成和血小板对维卡格雷的反应，并且如果未来上市时维卡格雷与阿司匹林同时服用，这种重要的药物间相互作用将会出现在临床环境中。
Abstract: Vicagrel, a novel acetate analogue of clopidogrel, exerts more potent antiplatelet effect than clopidogrel in rodents. Relevant evidence indicated that aspirin and vicagrel are the drug substrate for carboxylesterase 2. Accordingly, it is deduced that concomitant use of aspirin could attenuate the bioactivation of and platelet response to vicagrel. To clarify whether there could be such an important drug–drug interaction, the differences in both the formation of vicagrel active metabolite H4 and the inhibition of adenosine diphosphate–induced platelet aggregation by vicagrel were measured and compared between mice treated with vicagrel alone or in combination with aspirin. The plasma H4 concentration was determined by liquid chromatography–tandem mass spectrometry, and the inhibition of platelet aggregation by vicagrel was assessed by whole-blood platelet aggregation. Compared with vicagrel (2.5 mg·kg−1) alone, concurrent use of aspirin (5, 10, or 20 mg·kg−1) significantly decreased systemic exposure of H4, an average of 38% and 41% decrease in Cmax and AUC0–∞ in mice when in combination with aspirin at 10 mg·kg−1, respectively. Furthermore, concomitant use of aspirin (10 mg·kg−1) and vicagrel (2.5 mg·kg−1) resulted in an average of 66% reduction in the inhibition of adenosine diphosphate–induced platelet aggregation by vicagrel. We conclude that aspirin significantly attenuates the formation of vicagrel active metabolite H4 and platelet response to vicagrel in mice, and that such an important drug–drug interaction would appear in clinical settings if vicagrel is taken with aspirin concomitantly when marketed in the future.