氯吡格雷是目前使用最广泛的抗血小板药物，是急性心肌梗死病人经皮冠状动脉介入治疗后抗血小板治疗的金标准。然而，仍有约15%-40%的冠心病患者在服用氯吡格雷后血小板活性并未受到有效抑制。现有的临床研究发现多药耐药蛋白（MDR1）基因多态性与氯吡格雷抵抗的发生有关，但是目前对于MDR1基因突变如何影响氯吡格雷药效的机制并不明确。因此本项目（1）使用MDR1基因敲除小鼠对氯吡格雷吸收分布展开研究；（2）使用多种模型考察MDR1对氯吡格雷的转运情况研究；（3）在动物水平和细胞水平上，探明MDR1基因对氯吡格雷药效产生影响的作用通路，确证MDR1基因是否通过改变肝内胆汁酸成分，影响FoxA2-PXR通路，对CYP3A4的调控，从而影响氯吡格雷药效，为临床合理应用氯吡格雷提供理论依据。

Dual-antibody therapy combined with aspirin and clopidogrel (CLP) is the standard of care for patients with acute myocardial infarction, with the primary goal of reducing re-obstruction and other coronary events. Existing clinical studies have found that the pharmacodynamic and pharmacokinetic characteristics of CLP are related to the MDR1 gene polymorphism, but there are contradictions between many studies. Therefore, this project intends to conduct an in-depth study on whether CLP can be transported by P-glycoprotein and whether the decrease in multidrug-resistance receptor 1 (MDR1) activity affects the metabolic activation and anti-platelet activity of CLP by affecting the expression of CYP3A4. On the one hand, we intend to evaluate the effects of MDR1 on the absorption and distribution of CLP on varies models, namely the pharmacokinetics study in MDR1 knock-out (KO) mice, the MDR1 vesicle method, MDCK-MDR1 monolayer cell method, and.CLP concentration in hepatic portal vein. On the other hand, MDR1 KO mice, hepatic primary cells, as well as hepatic cell lines were used to examine the mechanisms of how MDR1 affects CYP3A4 activity. Therefore, it provides a theoretical basis for clinical rational use of CLP.