基于代谢组学的PK-PD研究阐释麝香保心丸的体内药效物质及其作用机制

SShexiang Baoxin pill, the Chinese Pharmacopoeia varieties, is one of the commonly used traditional Chinese medicine formula for the treatment of coronary heart disease. In our previous research, chemical constituents, qulity control, and pharmacological effects had been conducted thoroughly. Therefore, 10 SCI papers have been published, and 2 patents been applied on the results of previous studies.On the basis of previous studies, in vivo pharmacodynamic substance and their meachanism research will be further carried out by PK-PD study based on metabonomics approach. Pharmacokinetic study of the blood components of SBP in the formula, single herb and single component dosing conditions will be carried out by comparing the pharmacokinetic differences.In vivo pharmacodynamic substance will be finally screened according to serum pharmacokinetics and comparing pharmacokinetic studies.In this project, the biomarkers are used as pharmacodynamic index for PK/PD study. According to the blood concentration of active components at different time points and the endogenous biomarker concentration relationship, a PK-PD model will be established, and the pharmacodynamic components and biomarkers association networks will be built as well. Using Cytoscape visualization and network topology parameters calculation, the similarities and differences between the formula and single drug pharmacokinetics network will be analyzed. Furthermore, multicomponent synergy pharmacokinetics network characteristics will be studied, and the interaction relationship between drug-drug, integration multicomponent synergic meachanism of Shexiang Baoxin pill will be then clarified.

麝香保心丸是中国药典收录品种，是临床用于治疗冠心病心绞痛的常用药物之一。前期研究中，本课题组对麝香保心丸的化学物质基础、质量控制标准、药理药效等方面进行了深入研究，研究成果已发表SCI论文10篇，申请专利2项。本项目在前期研究基础上，采用基于代谢组学的PK/PD研究进一步阐释麝香保心丸进入体内的药效物质基础及其协同整合作用机制。根据入血成分在全方、单味药及单组分给药情况下的药代动力学差异，结合血清药化研究结果确定其体内药效物质。以代谢组学研究发现的生物标志物为药效指标进行PK/PD建模，构建药效组分与生物标志物关联网络。将药效组分-生物标志物关联网络映射到疾病生物标志物构建药效物质群-生物标志物网络，用Cytoscape可视化并计算网络拓扑参数并分析全方和单味药药代动力学网络的异同，研究多组分协同的药代动力学网络特征，阐释药物-药物的相互作用关系，解析麝香保心丸多组分协同的整合作用机制。

麝香保心丸是中国药典收录品种，是临床用于治疗冠心病心绞痛的常用药物之一。本课题组在对麝香保心丸的化学物质基础、质量控制标准、药理药效、代谢组学、药代动力学等方面深入研究的基础上，采用基于代谢组学的PK/PD研究进一步阐释麝香保心丸进入体内的药效物质基础及其协同整合作用机制。本项目共鉴定不同时间点MI大鼠的34个生物标志物，建立了基于疗效指数全面评价MI治疗作用的PK/PD模型，分别评价各时间点麝香保心丸中5种人参皂苷 (Rg1、Rb1、Rb3、Re及Rc)对MI模型大鼠生物标志物的调控作用效果，发现麝香保心丸中的人参皂苷类成分主要通过改善心梗后氧化损伤、纠正能量代谢紊乱、改善炎症等作用发挥药效。共鉴定不同时间点AMI大鼠的30个生物标志物，建立了基于疗效指数全面评价MI治疗作用的PK/PD模型，分别评价各时间点麝香保心丸中7种蟾蜍甾二烯类成分（酯蟾毒配基、蟾毒灵、日蟾毒他灵、远华蟾毒精、蟾蜍毒素、蟾毒他灵和蟾毒精）对AMI模型大鼠生物标志物的调控作用效果，发现麝香保心丸中的蟾蜍甾二烯类成分主要通过改善急性心梗后氧化损伤、纠正能量代谢紊乱等作用发挥药效。生物信息学研究结果表明，麝香保心丸全方对心血管疾病的治疗作用物质基础主要是入血成分，药物作用于疾病并不是全部直接作用于疾病的直接致病基因，而是通过网络的形式来对基因进行调控，从而达到治疗的目的。研究进一步证实了麝香保心丸中的入血成分肉桂醛具有促进血管新生的活性。肉桂醛参与调节细胞的各生物学活性及促进血管新生作用与c-Raf/MEK/Erk1/2信号通路及PI3K/AKT/eNOS信号通路紧密相关。..