基于CYP450酶CYP3A4和CYP2C9诱导与抑制的丹参与氯沙坦相互作用的研究方法

针对常用的中西药物相互作用研究方法的局限性和片面性，本项目以传统中药丹参和西药氯沙坦为研究示范，综合运用药代动力学，分子生物学等多学科手段，从分子-细胞-整体动物水平，创新构建基于CYP450酶的系统研究方法。该研究方法将整体分析（中西药联合用药的药代动力学研究）和分子水平分析（中药有效成分对药物代谢酶系统影响的研究）相结合，首次采用高效液相色谱-质谱法考察SD大鼠体内丹参片对氯沙坦及活性代谢物EXP3174的药代动力学影响，并研究丹参主要化学成分在Chang Liver细胞中对CYP3A4、CYP2C9蛋白和基因表达的影响，分析丹参有效成分对CYP450酶活性影响与氯沙坦药代动力学改变的相关性，从CYP450酶活性的角度阐明丹参与氯沙坦相互作用的分子基础，为丹参制剂在临床上的合理应用提供理论指导，也为基于CYP450酶的药物相互作用的研究开拓新的方法。

In terms of one-sidedness and limitations of common method of chinese-western drug interaction, this study exemplified traditional chinese medicine Salvia miltiorrhiza Bunge (SM) and western medicine losartan (Los), applied several tools and approaches based on multidisciplinary including pharmacokinetics and molecular biology, to make innovations to construct system method based on CYP450 enzyme from molecular-cell-whole animal level. This study combined analyses on integrity level (pharmacokinetic study of chinese-western medicine) and molecular level (effects of chinese herbs on drug metabolizing enzyme system), to study possible interaction in drug metabolism level. In this study, effects of SM on the pharmacokinetics of Los and EXP3174 were firstly detected by HPLC-MS. Effects of SM and its chemical compositions on the protein and gene expression of CYP3A4, CYP2C9 in Chang liver cells were detected. The relationship between effective compositions of SM on CYP450 enzyme activity and pharmacokinetics change of Los was analysed. This method can not only investigate the molecular basis of the interactions between SM and Los based on CYP450 enzyme activity, but also provide theoretical guidance for the reasonable application of SM in clinical, and explore innovative methods on drug interaction research based on CYP450 enzyme.