基于异功散中陈皮对肠吸收动力学影响的“补而不滞”配伍机制研究

Adding a little of activating qi medicine or blood-activating medicine etc, into tonifying Chinese medicine can make Chinese tonic prescription tonify without stagnation, that is a basic Traditional Chinese prescription compatibility theory. However, there are not in-depth and systematic studies on the effect and mechanism of “tonifying without stagnation” up to now.This project proposes a hypothesis that “Pericarpium Citri Reticulatae can influence the Yigong powder’s intestinal absorption kinetics which process is one of mechanisms of tonifying without stagnation”.In order to reveal the effect and mechanism of “tonifying without stagnation”, we select Yigong Powder prescription as a representative prescription of tonic and Pericarpium Citri Reticulatae as a representive of activating qi medicine.Experimental selection syndrome of deficiency of spleen qi model rats situ perfusion method in rats, the Coca-2 cell model method,and combined with drug transporter protein P-gp，ginsenoside Rb1、Re、Rg1 as detection Component detected with LC-MS method.Detection method by using liquid and mass spectrometry.We observe the difference of Yigong Powder prescription full party、only lack of Pericarpium Citri Reticulatae party、only lack of Radix Glycyrrhizae party and lack of Pericarpium Citri Reticulatae Radix Glycyrrhizae party in intestinal absorption kinetics process.And verified by PK-PD and pharmacodynamics.which can reveal the mechanism of “tonifying without stagnation”. We hope carry out this project with multi-discipline research methods, hoping it can expand the research ideas and methods of traditional Chinese prescription compatibility theory, and develop and perfect the theory. In addition, it has great significance to the research of traditional Chinese prescription’s pharmacokinetics and drug interaction rules by our project’s in-depth research of drug intestinal absorption characteristic and analysis the influence factors of prescription absorption.

方剂配伍理论认为，在补虚药中加入少量行气、活血药等药物，能使补益剂“补而不滞”，然而目前尚未对“补而不滞”的作用及作用机理进行深入系统的研究。本课题提出“陈皮影响异功散的肠吸收动力学过程，为其发挥“补而不滞”作用的机制之一”的假说，以异功散作为补益剂代表方，陈皮作为行气代表中药，采用脾气虚证模型大鼠在体肠灌流、Coca-2细胞模型，并结合药物对转运蛋白P-gp的影响，以人参皂苷Rb1、Re、Rg1和白术内酯I为检测指标，运用液质联用的检测方法，观察异功散全方、减陈皮方、减甘草方、减陈皮甘草方肠吸收动力学的差异，并通过PK-PD研究进行验证，以期通过多学科融合的研究手段，揭示“补而不滞”的作用及作用机理，为拓展方剂配伍理论的研究思路和方法，进而发展和完善方剂配伍理论打下基础。深入研究药物肠吸收特性，分析影响方剂吸收的因素，对研究方剂体内药代动力学过程和药物相互作用规律具有重要的意义。

方剂配伍理论认为，在补虚药中加入少量行气、活血药等药物，能使补益剂“补而不滞”。本课题提出“陈皮影响异功散的肠吸收动力学过程，为其发挥’补而不滞’作用的机制之一”的假说，以异功散作为补益剂代表方，陈皮作为行气代表中药，进行脾气虚证模型大鼠在体单向肠灌流试验、Coca-2细胞模型细胞转运试验，并结合P-gp抑制剂维拉帕米或P-gp激动剂利福平观察药物对转运蛋白P-gp的影响，以人参皂苷Rb1、Re、Rg1为检测指标，运用液质联用的检测方法，观察异功散全方、减陈皮方、减甘草方、减陈皮甘草方肠吸收动力学的差异，并采用PK-PD结合模型进行研究。. 结果显示，脾气虚证模型大鼠在体单向肠灌流试验中，陈皮能够显著促进异功散中人参皂苷Rb1、Re的肠吸收；Caco-2细胞模型细胞转运实验中，陈皮能够显著促进人参皂苷Rb1、Rg1、Re的肠吸收。人参皂苷Rb1、人参皂苷Re、人参皂苷Rg1的肠吸收机制可能与P-gp的转运有关，陈皮可能通过抑制P-gp以促进人参皂苷Rb1的肠吸收。陈皮能够促进异功散中人参皂苷Rb1吸收和分布的体内过程，能帮助异功散促进胃动素（MTL）的分泌；陈皮能使异功散中人参皂苷Rb1与MTL之间的亲和力更强、相关性更高，陈皮促进MTL分泌增多可能与人参皂苷Rb1肠吸收增多有关。. 以上研究证实，陈皮可促进异功散中君药人参的主要有效成分人参皂苷Rb1的肠吸收，其作用机制之一为抑制肠道P-gp以减少人参皂苷Rb1与之结合，使人参皂苷Rb1吸收入血的量更多速率更快，且分布范围更集中于效应部位，继发促进胃肠动力调节相关指标胃动素（MTL）的分泌增加，从而发挥“补而不滞”的配伍作用。. 通过研究陈皮对异功散肠吸收动力学的影响及影响机制，阐明了行气药配伍在补益方中，发挥“补而不滞”作用的部分作用机理，本课题对于阐释方剂配伍理论进行了有益的探讨。