Clopidogrel hydrogen sulfate is an orally effective purine-type P2Y12 receptor antagonist. The IC50 values for cytochrome P450 (CYP) subtypes CYP2B6 and CYP2C19 are 18.2nM and 524nM, respectively [1-2]. The P2Y12 receptor combines with the Gq pathway and promotes the release of intracellular calcium ions, thereby regulating the shape changes and aggregation process of platelets [3]. Clopidogrel hydrogen sulfate is a potent antithrombotic drug that can inhibit platelet aggregation triggered by adenosine diphosphate (ADP) [4].
In vitro, Clopidogrel hydrogen sulfate (0.5, 1.5mM; 24, 48h) upregulated the mRNA expression levels of TRIB3 and CHOP in GES-1 cells in a concentration- and time-dependent manner [5]. Clopidogrel hydrogen sulfate (1, 10 and 100μM; 24h) treatment concentration-dependently increased the cytotoxicity and intracellular ROS levels of HepG2 cells (expressing human CYP3A4) [6].
In the body, Clopidogrel hydrogen sulfate (1.25, 2.5, 3.75 and 5mg/kg; twice; gavage) can significantly inhibit thrombosis formation in a dose-dependent manner in the mouse arterial thrombosis model. When combined with acetylsalicylic acid (0.15mg/kg), it can enhance the antithrombotic effect of Clopidogrel hydrogen sulfate, while acetylsalicylic acid (0.6mg/kg) can weaken its antithrombotic effect [7]. 24 hours before the ischemia-reperfusion surgery, oral administration of Clopidogrel hydrogen sulfate (25mg/kg/day) significantly reduced the plasma levels of blood urea nitrogen (BUN) and creatinine in mice with renal ischemia-reperfusion injury (IRI), increased the expression of Bcl-2 and Bcl-xL, caspase-3 and caspase-8, and decreased the number of CD41-positive cells [8].
References:
[1] Laine L, Hennekens C. Proton pump inhibitor and clopidogrel interaction: fact or fiction?. Am J Gastroenterol. 2010;105(1):34-41.
[2] Katsunobu Hagihara, et al. Comparison of human cytochrome P450 inhibition by the thienopyridines prasugrel, Clopidogrel, and ticlopidine. Drug Metab Pharmacokinet. 2008;23(6):412-20.
[3] Dorsam R T, Murugappan S, Ding Z, et al. Clopidogrel: interactions with the P2Y12 receptor and clinical relevance[J]. Hematology, 2003, 8(6): 359-365.
[4] Herbert JM, Savi P. P2Y12, a new platelet ADP receptor, target of clopidogrel. Semin Vasc Med. 2003;3(2):113-122.
[5] Wu HL, Duan ZT, Jiang ZD, Cao WJ, Wang ZB, Hu KW, Gao X, Wang SK, He BS, Zhang ZY, Xie HG. Increased endoplasmic reticulum stress response is involved in clopidogrel-induced apoptosis of gastric epithelial cells. PLoS One. 2013 Sep 13;8(9):e74381.
[6] Zahno A, Bouitbir J, Maseneni S, Lindinger PW, Brecht K, Krähenbühl S. Hepatocellular toxicity of clopidogrel: mechanisms and risk factors. Free Radic Biol Med. 2013;65:208-216.
[7] Ni R, Vaezzadeh N, Zhou J, Weitz JI, Cattaneo M, Gross PL. Effect of Different Doses of Acetylsalicylic Acid on the Antithrombotic Activity of Clopidogrel in a Mouse Arterial Thrombosis Model. Arterioscler Thromb Vasc Biol. 2018 Oct;38(10):2338-2344.
[8] Hu H, Batteux F, Chéreau C, et al. Clopidogrel protects from cell apoptosis and oxidative damage in a mouse model of renal ischaemia–reperfusion injury[J]. The Journal of pathology, 2011, 225(2): 265-275.
Clopidogrel hydrogen sulfate是一种口服有效的嘌呤能P2Y12受体拮抗剂，对细胞色素P450（CYP）亚型CYP2B6和CYP2C19的IC50值分别为18.2nM和524nM [1-2]。P2Y12受体与Gq通路相结合，并促使细胞内钙离子释放，从而调节血小板的形状变化和聚集过程 [3]。Clopidogrel hydrogen sulfate是一种强效的抗血栓药物，能够抑制二磷酸腺苷（ADP）引发的血小板聚集 [4]。
在体外，Clopidogrel hydrogen sulfate（0.5, 1.5mM; 24, 48h）以浓度和时间依赖性方式上调了GES-1细胞中TRIB3和CHOP的mRNA表达水平 [5]。Clopidogrel hydrogen sulfate（1, 10和100μM; 24h）处理浓度依赖性地增加了对HepG2细胞（表达人类CYP3A4）的细胞毒性和细胞内ROS的水平 [6]。
在体内，Clopidogrel hydrogen sulfate（1.25, 2.5, 3.75和5mg/kg; 共两次; 灌胃）能够以剂量依赖性方式显著抑制小鼠动脉血栓形成模型中血栓的形成。与乙酰水杨酸（0.15mg/kg）合用可以增加Clopidogrel hydrogen sulfate的抗血栓形成作用，而乙酰水杨酸（0.6mg/kg）会减弱其抗血栓形成作用 [7]。在缺血再灌注手术前24小时通过口服Clopidogrel hydrogen sulfate（25mg/kg/day）显著降低了肾缺血再灌注损伤（IRI）小鼠血尿素氮（BUN）和肌酐的血浆水平，增加了Bcl-2和Bcl-xL、caspase-3和caspase-8表达降低，并减少了CD41阳性细胞的数量 [8]。