基于体内过程的三七-红花药对抗心肌缺血配伍增效机制研究

On the basis of our previous research, the synergy effects of Panax notoginseng and Carthamus tinctorius herb pair compatibility based on multi-component pharmacokinetics, drug-drug interaction and metabonomics will be performed in normal and myocardial ischemia model rats. In this project, UPLC-MS/MS technique for qualification and quantification is used combining with human induced hepatocytes (hiHeps), a new model for metabolic research in vitro and protein absolute quantification of abundance. First of all, the metabolic profiling and pharmacokinetic parameters of exogenous drugs in rats will be compared after oral administration of herb pair compatibility. Then, the effects on the activities and expression of CYPs, UGTs, and P-gp, MRP2 and BCRP transporters will be investigated, which could explore the mechanism of pharmacokinetic interactions between Panax notoginseng and Carthamus tinctorius. Finally, the metabonomics technique is used to analysis the change of endogenous biomarkers, which could reveal the effects on regulating metabolic pathways. According to above investigations, synergistic mechanism of Panax notoginseng and Carthamus tinctorius herb pair compatibility for treating myocardial ischemia could be explained from the whole animal, cellular and molecular levels. It will provide demonstration for research on compatibility theory and mechanism of TCM formulas, and possess scientific significance to guide clinical rational administration and to promote research and development of TCM formulas.

本课题在前期工作基础上，以正常大鼠、心肌缺血大鼠为模型，采用UPLC-MS/MS为定性、定量手段，结合创新的hiHep细胞体外代谢模型和蛋白质绝对定量方法，开展基于多组分体内药代动力学、药动学相互作用和代谢组学的三七-红花有效组分药对的配伍机制研究。通过比较单味药和复方体内成分的经时变化过程及规律，揭示药对配伍对药动学参数的改变；通过药对配伍对药物代谢酶CYP和UGT及转运体P-gp、MRP2和BCRP活性和蛋白表达的影响，揭示三七与红花之间的药动学相互作用；通过代谢组学手段，观察配伍前后内源性生物标志物的改变，阐述药对配伍对调节代谢通路的影响。综合上述研究，实现从整体动物—细胞水平—分子水平逐步深入地阐明中药三七-红花药对抗心肌缺血的配伍增效机制，揭示复方药效物质基础和作用机理，为中药复方配伍理论、作用机制的研究提供示范和参考，同时为该药对的新药研发及临床合理用药提供理论依据和指导。

本课题在前期工作基础上，以正常大鼠、心肌缺血大鼠为模型，采用UPLC-MS/MS为定性、定量手段，结合创新的hiHep细胞体外代谢模型和微流控芯片技术，开展基于多组分体内药代动力学、药动学相互作用和代谢组学的三七-红花有效组分药对的配伍机制研究。通过比较单味药和复方体内成分的经时变化过程及规律，揭示药对配伍对药动学参数的改变；通过药对配伍对药物代谢酶CYP和UGT蛋白表达的影响，揭示三七与红花之间的药动学相互作用；通过代谢组学手段，观察配伍前后内源性生物标记物的改变，阐述药对配伍对调节代谢通路的影响。综合上述研究，实现从整体动物—细胞水平—分子水平逐步深入地阐明中药三七-红花药对抗心肌缺血的配伍增效机制，揭示复方药效物质基础和作用机理，为中药复方配伍理论、作用机制的研究提供示范和参考，同时为该药对的新药研发及临床合理用药提供理论依据和指导。