代谢-转运互作介导糖/脂代谢异常机体中丹参制剂调控阿托伐他汀药动学的分子机制

阿托伐他汀(ATR)是临床常用的降脂药，糖尿病患者服用其高剂量时肌痛和肝脏毒性发生率高，严重者可致肌坏死和肝损伤。ATR是肝肠代谢酶/转运体的底物，在联合用药中存在风险。因此亟待明确ATR体内药物浓度的影响因素，从源头上阻止不良反应的发生。. 基于前期发现ATR与丹参素联用时，其药动参数被显著改变。本项目拟采用代谢-转运互作模式，以高糖高脂动物为疾病模型，明确丹参制剂调节ATR代谢、转运的表征与内在关系，明确长期联用对组织摄取调控、组织毒性及生化指标的影响；采用Bio-PK/三明治细胞模型探讨代谢酶、转运体介导两药内在关系及在人体的处置；采用转染细胞、基因敲除鼠等技术，从核受体、蛋白表达及整体角度初步阐明代谢酶、转运体基因多态性对两药相互作用的影响。该项目的实施，将为精准探究他汀类联用的靶点，深入评价临床联用毒性的分子机制，发现药物临床使用安全性的关键问题具有重要价值。

Atorvastatin (ATR) is a commonly used lipid-regulating drug. It is clinically found that after taking high-dose atorvastatin in diabetic patients, the incidence of adverse reactions such as muscle pain and liver toxicity is higher than that in non-diabetic patients. Patients with severe adverse reactions may even have muscle necrosis and liver damage. At the same time, ATR is also a substrate for metabolic enzymes / transporters. When ATR is taken in combination with other drugs, there may be potential drug safety risks. Therefore, it is urgent to clarify the reason for the change in the concentration of ATR in the blood, so as to essentially prevent the occurrence of adverse reactions of atorvastatin.. This study was based on the previous discovery that when ATR was combined with Danshensu, its pharmacokinetic parameters were significantly changed. Now, using the concept of the interaction of metabolic enzymes and transporters to study the disease model of hyperlipidemic and hyperglycemic animals, explore the characteristics and internal relationship of Salvia miltiorrhiza regulating ATR metabolism and transport, discover the effect of long-term combined use of ATR and Salvia miltiorrhizae on pharmacokinetic changes on liver uptake, tissue toxicity and blood biochemical indicators in animals. Using the Bio-PK/sandwich cell transport model to explore the regulatory relationship between metabolic enzymes and transporters after using Salvia miltiorrhiza and ART in combination, and predict the metabolic disposal of atorvastatin in the human after using Salvia miltiorrhiza and ART simultaneously. Using transfected cells, gene knockout mice and other techniques, from the perspective of nuclear receptors, protein expression and the overall point of view, the effects of metabolic enzymes and transporter gene polymorphisms on the interaction of the two drugs are preliminarily clarified. The implementation of this study will accurately explore the molecular targets of statin drug combination, in-depth evaluation of the molecular mechanism of the potential toxicity of clinical combination drugs, and discover the key issues of clinical safety of listed drugs with important application value.