基于药效物质组及肝肾转运体排泄网络研究生脉方“君臣佐”配伍理论的药动学机制

方剂核心是药物配伍，采用现代方法从药动学角度探究中药配伍后药效物质组的变化规律是关键。在肝肾排泄系统中分布着复杂的药物转运体网络，中药复杂组分可以经肝肾转运排泄或对转运功能产生影响。生脉方配伍理论中可能蕴含着不同药味间的药效物质组发生基于肝肾转运体网络介导的竞争，导致排泄减少、药效增强的协同配伍机制。前期证实参麦方中Rb1和Rd显著抑制OATP1B1/1B3-HEK293T细胞中OPD的摄取，联用Rb1+Rd后大鼠体内OPD血药浓度明显升高，提示参麦方复杂组分间存在基于OATPs介导的相互作用。课题拟构建系列高表达肝肾转运体的细胞模型，系统研究生脉方主要药效物质组在肝肾转运体网络介导下的转运情况、对转运功能的影响及其配伍前后转运变化；研究单独与配伍给药后大鼠体内目标成分群的血肝分布、胆尿排泄及其对转运体表达调控，从肝肾转运体排泄网络角度阐明生脉方“君臣佐”配伍理论的科学内涵及药动学机制。

Prescription compatibility is the core for Chinese medicinal formulae and exploring the variation rules of the active ingredient groups after combination based on pharmacokinetic perspective by using modern methods will be very crucial. A series of transporters distribute in hepatic and renal excretory system and can transport the complex constituents of Traditional Chinese Medicine (TCM). These constituents from TCM maybe also influence the activities of above transporters. The compatibility theory of ShengMai Formula (SMF) may imply a synergistic combination mechanism that competitions or regulations may occur among the active ingredient groups from different herbs in SMF mediated by hepatic and renal transporters network and result in the decrease of drug excretion and the enhancement of drug action. Our previous studies indicate that Rb1 and Rd significantly inhibit the uptake of ophiopogonin D (OPD) in OATP1B1/1B3-HEK293T cells, and OPD’s plasma concentrations in rats obviously rise after combination with Rb1 and Rd, which suggests there maybe some interactions among the complex constituents in ShenMai Injection mediated by OATPs. In this project, therefore, we will construct a series of overexpressing hepatic or renal transporter cell models and systematacially study the transporting mechanisms of the principal constitutions of Shengmai Formula mediated by hepatic and renal transporters network. Their impacts on transporters’ functions and the variations of their transporting process after compatibility also need to be explored. Furthermore, we also will investigate the profiles of distribution of target ingredients in blood and liver and its elimination from bile and urine ducts in rats when single or combined administration. The purpose is to illustrate the compatibility mechanisms of different active ingredient groups from “Monarch, Minister and Assistant” in SMF and its scientific connotation in terms of hepatic and renal transporter network.