氯吡格雷为前体药物，需体内吸收代谢后发挥抗血小板作用，在心脑血管疾病等领域应用广泛，但仍有部分患者因存在氯吡格雷抵抗而发生血栓事件，亟需有效方法加以改善。三七总皂苷具有活血祛瘀、通脉活络的功效，其与氯吡格雷的联用在临床上已初显疗效，但具体机制尚未明确。课题组前期实验显示三七总皂苷对氯吡格雷具有协同增效作用，并提示与氯吡格雷活性代谢物增加有关。因此，本项目拟进一步探索三七总皂苷对氯吡格雷协同作用的量效和时效关系；并从氯吡格雷的吸收和代谢途径出发，采用Caco-2和MDCK-MDR1细胞模型研究三七总皂苷对P-糖蛋白介导的氯吡格雷吸收的影响，以大鼠和人原代肝细胞模型研究其对CYP2C19介导的氯吡格雷代谢活化的影响，并选用人羧酸酯酶-1模型研究其对氯吡格雷代谢失活通路的影响。由此揭示三七总皂苷协同增效的确切机制，为中西医结合处置氯吡格雷抵抗提供科学依据，推动中成药在临床抗血栓中的应用研究。

As a prodrug, clopidogrel is activated to display antiplatelet effect via absorption and metabolism, and it is widely used in clinic for the treatment of cardiovascular and cerebrovascular diseases. While some patients still occur thrombus due to their poor response to clopidogrel. Therefore, it’s urgent to find an efficient way to resolve this problem. Panax notoginseng saponins (PNS) demonstrated “huoxue quyu” and “tongmai huoluo” effects in clinic, and its combination with clopidogrel has showed synergetic effect, while the exact mechanism remains unclear. Our previous work revealed that this synergetic effect of PNS was related with the increase of clopidogrel active metabolite. Thus, this project will clarify the dose-effect and time-effect relationship of PNS to clopidogrel. To elucidate clearly the synergistic mechanism of PNS with clopidogrel, this project will study the effect of PNS on the absorption and metabolism of clopidogrel and carry out extensive research in following three directions. Firstly, evaluate the effect of PNS on P-glycoprotein mediated clopidogrel absorption using Caco-2 and MDCK-MDR1 cell model. Secondly, investigate the induction effect of PNS on CYP2C19 using rat and human primary hepatocytes model. Thirdly, evaluate the carboxylesterase-1 inhibitory activity of PNS using human carboxylesterase-1 model. The project will provide scientific basis for the combination of PNS in disposal of clopidogrel resistance, and promote the use of traditional Chinese medicine in antithrombotic therapy.