From the Department of Internal Medicine, Cardiovascular Research Center, University of Michigan Medical Center, Ann Arbor (Y.S., J.V., C.G., Y.F., Y.E.C., D.T.E.).
Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, China (Y.S.).
Arterioscler Thromb Vasc Biol. 2020 Jun;40(6):1533-1542. doi: 10.1161/ATVBAHA.120.314146. Epub 2020 Apr 9.
Clopidogrel is a commonly used P2Y inhibitor to treat and prevent arterial thrombotic events. Clopidogrel is a prodrug that requires bioactivation by CYP (cytochrome P450) enzymes to exert antiplatelet activity. Diabetes mellitus is associated with an increased risk of ischemic events, and impaired ability to generate the active metabolite (AM) from clopidogrel. The objective of this study is to identify the mechanism of clopidogrel resistance in a murine model of diet-induced obesity (DIO). Approach and Results: C57BL/6J mice and IL-1R mice were given high-fat diet for 10 weeks to generate a murine model of diet-induced obesity. Platelet aggregation and carotid arterial thrombosis were assessed in response to clopidogrel treatment. Wild-type DIO mice exhibited resistance to antiplatelet and antithrombotic effects of clopidogrel that was associated with reduced hepatic expression of CYP genes and reduced generation of the AM. IL (Interleukin)-1 receptor-deficient DIO (IL1R DIO) mice showed no resistance to clopidogrel. Lack of resistance was accompanied by increased exposure of the clopidogrel AM. This resistance was also absent when wild-type DIO mice were treated with the conjugate of the clopidogrel AM, DT-678.
These findings indicate that antiplatelet effects of clopidogrel may be impaired in the setting of diabetes mellitus due to reduced prodrug bioactivation related to IL-1 receptor signaling. Therapeutic targeting of P2Y in patients with diabetes mellitus using the conjugate of clopidogrel AM may lead to improved outcomes.
氯吡格雷是一种常用于治疗和预防动脉血栓事件的 P2Y 抑制剂。氯吡格雷是一种前药，需要细胞色素 P450（CYP）酶生物激活才能发挥抗血小板作用。糖尿病与缺血性事件风险增加以及从氯吡格雷生成活性代谢物（AM）的能力受损有关。本研究旨在确定饮食诱导肥胖（DIO）小鼠模型中氯吡格雷耐药的机制。
C57BL/6J 小鼠和 IL-1R 小鼠给予高脂肪饮食 10 周，以生成饮食诱导肥胖的小鼠模型。评估氯吡格雷治疗对血小板聚集和颈动脉动脉血栓形成的影响。野生型 DIO 小鼠对氯吡格雷的抗血小板和抗血栓作用产生耐药性，这与肝 CYP 基因表达减少和 AM 生成减少有关。IL-1 受体缺陷型 DIO（IL1R DIO）小鼠对氯吡格雷无耐药性。缺乏耐药性伴随着氯吡格雷 AM 的暴露增加。当用氯吡格雷 AM 的缀合物 DT-678 治疗野生型 DIO 小鼠时，这种耐药性也不存在。
这些发现表明，由于与 IL-1 受体信号相关的前药生物激活减少，糖尿病患者中氯吡格雷的抗血小板作用可能受损。使用氯吡格雷 AM 的缀合物在糖尿病患者中靶向 P2Y 可能会改善结局。
