基于吸收仿生模型研究P-gp介导的银杏叶-他林洛尔相互作用及其体内外关联性

Studies on herb-drug interactions (HDI) are increasingly receiving attention. In vitro absorption bionic system can simulate continuous dynamic process of drug dissolution in the stomach, its movement to the intestinal tract, and then permeation through intestinal mucosa. The purpose of this project is to establish a bionic system (DDASS) for the study of drug absorption and HDI that is intestinal P-gp-mediated. For the evaluation of HDI mediated by P-gp in this study, ginkgo biloba is selected as a model herbal medicine and talinolol as a probe drug. Cell culture model, in vitro bionic system and human model were employed, to respectively evaluate the effect of the main active constituent, active fraction standard extract (EGb 761) and the commercial EGb 761 preparation of ginkgo leaf on the absorption of talinolol. The interactions between talinolol and pharmacodynamic material basis of ginkgo biloba and their absorption mechanisms will be analyzed from target transporter of P-gp. A three dimensional correlation on talinolol tablet was developed between DDASS dissolution - transmembrane permeation in vitro and absorption in vivo. It is expected that an evaluation and prediction system for HDI mediated by P-gp, will be established. Furthermore, it will provide theoretical and practical basis on improving the clinical rational use of drug and reducing the occurrence of adverse reactions.

中草药-药物相互作用（HDI）研究日益受到人们关注。体外吸收仿生系统可以连续、动态地模拟药物在胃内溶解、移行至肠道以及透过肠粘膜吸收的过程。本课题旨在建立基于药物溶出/吸收仿生系统（DDASS）研究肠道P-gp介导的HDI预测评价体系。基于"中草药-P-gp-化学药吸收相互作用"研究思路，拟以他林洛尔为探针药，以银杏叶为模型中草药，抽取有效组分萜类内酯和黄酮醇苷为基本单元，在细胞模型、体外仿生模型和整体动物模型三个水平，分别解析银杏叶主要有效成分、有效组分、标准提取物（EGb761）及其市售提取物制剂金纳多对他林洛尔吸收的影响。从肠道P-gp角度探讨合并用药对探针药in vitro跨膜透过和in vivo药动学终点参数的影响， 构建他林洛尔片在DDASS溶出-跨膜透过-人体内吸收的三维关联性。以期构建基于高内涵的DDASS研究P-gp介导HDI的预测评价体系，为指导临床合理用药奠定基础。

中草药-药物相互作用（HDI）研究倍受到人们关注。体外吸收仿生系统可以连续、动态地模拟药物在胃内溶解、移行至肠道以及透过肠粘膜吸收的过程。本课题旨在建立基于药物溶出/吸收仿生系统（DDASS）研究肠道P-gp介导的HDI预测评价体系。借助"中草药-P-gp-化学药吸收相互作用"研究思路，本课题组开展了：（1）基于胃肠道多元医学信息驱动的DDASS预测体系的构建及验证；（2）基于细胞吸收模型、体外动态仿生模型、在体肠灌流模型和Beagle犬整体模型研究 P-gp介导的银杏叶-他林洛尔相互作用及体内外相关性；（3）基于细胞吸收模型、在体肝灌流模型和Beagle犬整体模型研究肝脏OATP1B1介导的EGB-匹伐他汀相互作用。该三部分研究发现：（1）阿呋唑嗪、双氯芬酸、单硝酸异山梨酯、美托洛尔、茶碱和青藤碱6个不同pKa的高渗透性药物缓释片在DDASS的溶出/跨膜透过与Beagle犬体内吸收存在显著体内外相关性（r>0.878）；TZQ-F的PK-markers在DDASS溶出（Fd）/跨膜透过（Fp）与人体吸收（Fa）经回归分析具有显著相关性。（2）EGB主要药效物质在MDCK-MDR1细胞模型对MDR1无显著抑制效应；他林洛尔与EGB合用前后，在DDASS溶出侧和透过测的药物浓度无显著变化；P-gp底物和BCRP底物与EGB合用前后，在大鼠在体单向肠灌流模型小肠的十二指肠、空肠、回肠的有效渗透百分数无显著性差异；他林洛尔与EGB合用前后在Beagle犬体内血药浓度变化不显著。（3）EGB中萜内酯成分在HEK293细胞对OATP1B1无抑制效应，而黄酮类成分显著抑制OATP1B1的摄入活性；EGB在大鼠在体肝灌流和Beagle犬对OATP1B1均有显著抑制效应，提高了匹伐他汀在体内BA。本课题组成功构建了基于高内涵的DDASS研究P-gp介导HDI的预测评价体系，为创新中药成药性研究提供新技术和新思路；阐明了“银杏叶-P-gp -他林洛尔”和“银杏叶-OATP1B1 -匹伐他汀”相互作用的物质基础及其作用机制，为临床合理用药奠定基础。已发表学术论文4篇，其中SCI论文1篇；已投稿待发表SCI论文2篇；荣获省部级科技进步奖2项；培养研究生2名、本科生4名。本项目实现了计划书的预期研究结果，并超额完成研究目标。