本课题旨在对氯吡格雷诱发他汀类药物肝损伤的作用机制进行研究。.他汀是当今临床使用最广泛的一类降脂药，疗效确切但不良反应常见，其中最关切的是横纹肌溶解作用，但近年来对其导致的肝损伤案例也时有报道，有研究指出抗血小板药氯吡格雷与之合用会诱发或加重肝损伤，而引起这一现象的机理至今尚不明确。鉴于临床上这两者有较高的合用频率，故从机制方面对其进行研究并找出切实可行的解决方案显得十分迫切和必要。.我们前期研究表明，氯吡格雷能够激活OATP1B1从而促进瑞舒伐他汀的肝脏摄取，而代谢物氯吡格雷羧酸抑制外排转运体BCRP和MRP2的功能而减少其外排。故推测这种双重作用导致瑞舒伐他汀在肝内大量积蓄而诱发损伤。.本课题拟以瑞舒伐他汀为工具药，利用相关细胞与生物学技术，从肝脏对药物摄取-外排的OATPs-BCRP/MRP2转运通路角度探究氯吡格雷诱发其肝损伤的作用机制，并提出解决方案，为临床合理应用提供重要参考。

The specific aim of this study is to explore the mechanism of clopidogrel-induced statin liver injury..Approximately 300 million Chinese receive statin therapy for hypercholesterolemia. While generally safe and effective, the use of statins is complicated by the infrequent but life-threatening liver injury, which is induced or aggravated in the presence of clopidogrel. However, the mechanism remains unknown. Considering the high frequency of using in combination in clinic, it is of great importance to conduct mechanistic study on clopidogrel- induced statin liver injury and find out feasible solutions..Our preliminary data show that, in clinical relevant concentrations, clopidogrel could stimulate OATP1B1 mediated rosuvastatin hepatic uptake, while its major metabolite, clopidogrel carboxylic acid, inhibit BCRP and/or MRP2 mediated rosuvastatin efflux. Therefore, we hypothesize that such dual effect on influx (e.g. activation of OATP1B1) and efflux (e.g. inhibition of BCRP and/or MRP2) transporters, causing significant increase in hepatic concentration, are determinants of liver injury..To do so, we will conduct studies on a representative statins, rosuvastatin. Various in vitro model including stable transfected transporter-overexpressing cell lines, vesicles, hepatocytes, and in vivo model including rats and modeling will be used. Analytic technique such as LC-MS/MS, western blot and real time PCR will also be applied. Based on OATPs-BCRP/MRP2 transporting network, this study could provide important insight into the mechanism(s) responsible for clopidogrel-induced statin liver injury. Moreover, the above study will provide clinicians guidelines as to when and by how much to adjust the dose of statin according to the magnitude and clinical significance of such drug drug interaction.