Enhanced Platelet Response to Clopidogrel in Abcc3-deficient Mice Due to Its Increased Bioactivation.
Enhanced Platelet Response to Clopidogrel in Abcc3-deficient Mice Due to Its Increased Bioactivation.
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Abcc3 缺陷小鼠中氯吡格雷的血小板反应增强，因为其生物活性增强。
DOI：
10.1097/fjc.0000000000000428
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发表时间：
2016
影响因子：
3
通讯作者：
Xie Hong-Guang
中科院分区：
文献类型：
--
作者：
Tai Ting;Mi Qiong-Yu;Ji Jin-Zi;Yin Qian;Pan Yu-Qin;Zhang Meng-Ran;Huang Bei-Bei;Xie Hong-Guang
最近有报道称，患者对氯吡格雷（一种无活性前药）的耐药性与编码MRP 3（多药耐药相关蛋白3）的ABCC 3信使RNA表达增加有关。然而，没有证据表明MRP3对改变的血小板对氯吡格雷的反应及其潜在机制的影响。为了进一步阐明Mrp3的存在或缺失是否会影响Abcc3基因敲除（KO）小鼠与野生型（WT）小鼠中氯吡格雷活性代谢产物（CAM）的形成和反应，我们测定了氯吡格雷和CAM的药代动力学特征，并分别测定了KO和WT小鼠单次口服氯吡格雷后氯吡格雷对二磷酸腺苷诱导的血小板聚集的抑制作用。结果表明，与匹配良好的WT小鼠相比，Abcc3 KO小鼠表现出CAM形成增加，氯吡格雷全身暴露量增加，氯吡格雷对二磷酸腺苷诱导的血小板聚集的体外抑制作用增强。我们的结论是，由于CAM的形成增加，Abcc 3基因敲除小鼠对氯吡格雷的血小板反应增强。
Resistance of the patient to clopidogrel (an inactive prodrug) has been recently reported to be associated with increased messenger RNA expression of ABCC3 that encodes MRP3 (multidrug resistance–associated protein 3). However, there is no evidence showing the effects of MRP3 on altered platelet responses to clopidogrel and their underlying mechanisms. To further clarify whether the presence or absence of Mrp3 could affect the formation of and response to clopidogrel active metabolite (CAM) in Abcc3 knockout (KO) versus wild-type (WT) mice, we determined pharmacokinetic profiles of clopidogrel and CAM and measured inhibition of adenosine diphosphate–induced platelet aggregation by clopidogrel after administration of a single oral dose of clopidogrel to KO and WT mice, respectively. Results indicated that Abcc3 KO mice exhibited increased formation of CAM and greater systemic exposure to clopidogrel and enhanced inhibition of adenosine diphosphate–induced platelet aggregation ex vivo by clopidogrel when compared with well-matched WT mice. We conclude that Abcc3 KO mice have enhanced platelet response to clopidogrel due to increased formation of CAM.