Ning Chen, Su Shengdi, Li Jiaming, Kong Dexuan, Cai Hui, Qin Zhiying, Xing Han, Chen Xijing, He Jiake
Department of Pharmacy, The Second Affiliated Hospital of Nanchang University, Nanchang, China.
Clinical Pharmacokinetics Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
Front Pharmacol. 2021 Sep 27;12:715577. doi: 10.3389/fphar.2021.715577. eCollection 2021.
The combination therapy of rosuvastatin (RSV) and the platelet inhibitor clopidogrel (CP) is widely accepted in the management of cardiovascular diseases. The objective of the present study was to identify the mechanism of RSV-CP DDI and evaluate the risk of hepatotoxicity associated with the concomitant use of CP. We first studied the effect of CP and its major circulating metabolite, carboxylic acid metabolite (CPC), on RSV transport by overexpressing cells and membrane vesicles. Second, we investigated whether a rat model could replicate this DDI and then be used to conduct mechanistic studies and assess the risk of hepatotoxicity. Then, cytotoxicity assay in hepatocytes, biochemical examination, and histopathology were performed to measure the magnitude of liver injury in the presence and absence of DDI. CP inhibited OATP1B1-mediated transport of RSV with an IC value of 27.39 μM. CP and CPC inhibited BCRP-mediated RSV transport with IC values of <0.001 and 5.96 μM, respectively. The CP cocktail (0.001 μM CP plus 2 μM CPC) significantly inhibited BCRP-mediated transport of RSV by 26.28%. Multiple p.o. doses of CP significantly increased intravenous RSV plasma AUC by 76.29% and decreased intravenous RSV CL by 42.62%. Similarly, multiple p.o. doses of CP significantly increased p.o. RSV plasma AUC by 87.48% and decreased p.o. RSV CL by 43.27%. CP had no effect on cell viability, while RSV exhibited dose-dependent cytotoxicity after 96 h incubation. Co-incubation of 100 μM CP and RSV for 96 h significantly increased intracellular concentrations and cell-to-medium concentration ratios of RSV and reduced hepatocyte viability. Histological evaluation of liver specimens showed patterns of drug-induced liver injury. Cholestasis was found in rats in the presence of DDI. CP is not a clinically relevant inhibitor for OATP1B1 and OATP1B3. The primary mechanism of RSV-CP DDI can be attributed to the inhibition of intestinal BCRP by CP combined with the inhibition of hepatic BCRP by CPC. The latter is likely to be more clinically relevant and be a contributing factor for increased hepatotoxicity in the presence of DDI.
瑞舒伐他汀（RSV）与血小板抑制剂氯吡格雷（CP）的联合疗法在心血管疾病管理中被广泛接受。本研究的目的是确定RSV-CP药物相互作用（DDI）的机制，并评估与CP联合使用相关的肝毒性风险。我们首先通过过表达细胞和膜囊泡研究了CP及其主要循环代谢物羧酸代谢物（CPC）对RSV转运的影响。其次，我们研究了大鼠模型是否可以复制这种DDI，然后用于进行机制研究和评估肝毒性风险。然后，在肝细胞中进行细胞毒性测定、生化检查和组织病理学检查，以测量存在和不存在DDI时肝损伤的程度。CP以27.39 μM的IC值抑制OATP1B1介导的RSV转运。CP和CPC分别以<0.001和5.96 μM的IC值抑制BCRP介导的RSV转运。CP鸡尾酒（0.001 μM CP加2 μM CPC）显著抑制BCRP介导的RSV转运26.28%。多次口服CP显著增加静脉注射RSV的血浆AUC 76.29%，并降低静脉注射RSV的CL 42.62%。同样，多次口服CP显著增加口服RSV的血浆AUC 87.48%，并降低口服RSV的CL 43.27%。CP对细胞活力无影响，而RSV在孵育96小时后表现出剂量依赖性细胞毒性。100 μM CP和RSV共同孵育96小时显著增加RSV的细胞内浓度和细胞与培养基浓度比，并降低肝细胞活力。肝脏标本的组织学评估显示出药物性肝损伤的模式。在存在DDI的大鼠中发现胆汁淤积。CP不是OATP1B1和OATP1B3的临床相关抑制剂。RSV-CP DDI的主要机制可归因于CP对肠道BCRP的抑制以及CPC对肝脏BCRP的抑制。后者可能在临床上更相关，并且是存在DDI时肝毒性增加的一个促成因素。
