基于效应成分PK-PD关联融合多目标优化的复方脑脉通体内过程及配伍规律研究

Compatibility and pharmacodynamic material basis of complex prescription are the core content of chinese medical science field of research. In this study, Naomaitong as a carrier, based on traditional Chinese medicine combined multi-component with multi-target comprehensive effects, using serum chemistry and urine metabolic chemistry method, to identify chemical composition in high exposure. Meanwhile, to carry out its multi-component pharmacokinetics and pharmacodynamic studies, using SVM, MR and fusion of multi-objective optimization methods to research on correlation between PK and PD, to quantitatively describe synergy and antagonism among the effect composition and the main and auxiliary status of corresponding medicine. And on the basis of evaluation parameters, conducting combinatorial pharmacokinetics(CPK) study through a quantitative combination of serum concentrations of the effect composition, to interpret overall pharmacokinetic characteristics and compatibility laws of Naomaitong and provide a scientific basis for its clinical rational use. The method of studying on the correlation between PK and PD of traditional Chinese medicine complex prescription multi-component bulit by using SVM fusion of multi-objective optimization bioinformatic methods provides a demonstration to pharmacokinetic study of traditional Chinese medicine. This article explores the research mode of complex prescription compatibility laws and pharmacodynamic action substance foundation, which is "Identification of chemical composition characterization of dynamic process - Effect composition of PK-PD correlation and its interaction mechanism confirmation - Combinatorial pharmacokinetics rules of multi-objective optimization", to provide reference for the study of compatibility laws in complex prescription.

中药复方配伍及物质基础研究是中医药研究的核心内容之一。本研究以脑脉通为载体，基于中药多成分多靶点综合作用特点，采用血清化学和尿液代谢化学方法，发现辨识体内高暴露的化学成分；同步开展其多成分药代动力学及药效动力学研究，采用SVM、MR并融合多目标优化方法进行PK-PD相关性研究，定量描述各效应成分相互间的协同与拮抗作用及其相应药味的主辅地位，并依据评价参数进行效应成分血清浓度的定量"组合"整合药代动力学研究，阐释脑脉通的整体药动学特征及其配伍规律，为脑脉通的临床合理用药提供科学依据。该研究采用的SVM融合多目标优化的生物信息学方法构建的中药复方多成分PK-PD相关性研究方法为中药复方药动学研究提供示范。同时探索建立"动态过程的化学成分表征辨识-PK-PD关联的效应成分及其互作机制确证-融合多药效目标优化的整合药动学规律"的中药复方配伍规律-物质基础研究模式，为中药复方配伍规律研究提供借鉴。

中药复方配伍及物质基础研究是中医药研究的核心内容之一。本研究以脑脉通为载体，基于中药多成分多靶点综合作用特点，采用血清化学和尿液代谢化学方法，发现辨识体内高暴露的化学成分；开展其多成分药代动力学及药效动力学研究，采用支持向量机（SVM）方法进行 PK-PD 相关性研究，定量描述各效应成分相互间的作用及其相应药味的主辅地位，并依据评价参数进行整合药代动力学研究。本研究建立了脑脉通的体外及体内动态效应成分谱，辨识出体内直接作用物质22个，其中10个来源于人参，2个来源于大黄，5个来源于葛根，5个来源于川芎。另外，本研究发现脑脉通中各味药的配伍较两味药对时增加入血成分种类；同时，脑脉通干预的大鼠血清中大黄酸、大黄素、芦荟大黄素、洋川芎内酯 I、藁本内酯、丁烯基苯酞、人参皂苷 Rb1、葛根素、和大豆苷等的达峰浓度（Cmax）及曲线下面积（AUC）水平基本优于各药对配伍组。初步阐明脑脉通各组方中多成分的体内量变规律。此外，本研究建立了缺血性脑中风体外四种细胞损伤模型，研究脑脉通成分对该四种神经元损伤模型的保护作用，确定各组方抗脑缺血损伤的药效差异；进而采用 SVM方法研究各组分的 PK 参数与抗神经元死亡效应的相关性，发现复方脑脉通整合后的药动学参数充分兼顾了各单味药中代表成分的药动学特征，其中3´-甲氧基葛根素、葛根素、大黄酸、人参皂苷Rb1、人参皂苷Rc等的贡献较大。本研究分析脑脉通各代表成分相应药味间的互作机制及其主辅等配伍地位，确定最佳配伍组合，为优化给药方案和临床合理应用提供科学依据。