基于SHR及其主动脉VEC在剪切力环境下的杜仲降血压活性成分的PK-PD结合模型研究

Eucommia ulmoides alone or in combination with Western medicine has a significant effect in the treatment of hypertension, which is one of important and famous traditional Chinese medicine in Guizhou Province. However, there are some difficulties to the further develop because the specific antihypertensive substance of Eucommia ulmoides is not clear. Pharmacokinetic-pharmacodynamic (PK-PD) link model can provide a scientific basis for elucidating the pharmacological basis of traditional Chinese medicine. Given the fact that traditional Chinese medicine is mainly used in the pathological state, the establishment of PK-PD link model of hypotensive ingredients in Eucommia ulmoides under pathological state will be essential. Importantly, we have found that the exposure of Pinoresinol diglucoside and geniposidic acid with the hypotensive effect contained in Eucommia ulmoides in spontaneously hypertensive rats (SHR) were significantly higher than that of normal rats. Therefore, in the present study, based on spontaneously hypertensive rats and vascular endothelial cell deriving from its aorta and cultured by shear stress, the PK-PD model of hypotensive active ingredients in Eucommia ulmoides will be established from the view of the pathological states and cell pharmacokinetics. The success of this study would further clarify the matter with directly hypotensive effect and provide the scientific basis for the further development of medicinal resources.

杜仲单用或与西药合用在治疗高血压方面疗效显著，为贵州省重点开发的中药材之一，然而杜仲具体的降压物质尚不清楚，已成为其深层次开发利用的技术瓶颈。药代动力学-药效动力学（PK-PD）结合模型可以为中药的药效物质基础阐明提供科学依据。鉴于中药主要是作用于病理状态的机体，因此建立病理状态下的杜仲降血压活性成分的PK-PD结合模型至关重要。申请人在前期研究中发现杜仲的潜在降压成分松脂醇二葡萄糖苷和京尼平苷酸在自发性高血压大鼠（SHR）体内的暴露量显著高于正常大鼠。有鉴于此，本课题拟在前期研究基础上，以SHR为动物模型，同时以其主动脉血管内皮细胞（VEC）为细胞模型，并对VEC施加一定的剪切力，以模拟高血压状态下的受损细胞，从病理状态和细胞药代动力学的角度，构建杜仲降血压活性成分的PK-PD结合模型，以期阐明杜仲在体内与降血压作用直接相关的药效物质，为其药用资源的深度开发奠定科学依据。

杜仲单用或与西药合用在治疗高血压方面疗效显著，为贵州省重点开发的中药材之一，但其药代动力学-药效动力学（PK-PD）结合模型研究尚属空白，已成为其深层次开发利用的技术瓶颈。因此，本课题在前期研究的基础上，以杜仲中松脂醇二葡萄糖苷（PDG）、京尼平苷酸（GA）、松脂醇单葡萄糖苷（PG）、原儿茶酸（PCA）、绿原酸（CA）、新绿原酸（NCA）、隐绿原酸（CCA）等7个成分作为药动学指标，首先以自发性高血压大鼠（SHR ）为动物模型，采用WinNonLin 8.2软件，结合整合药代动力学的思路，建立杜仲的PK-PD结合模型：以AngⅡ为药效指标时，杜仲中各成分整合后的PK-PD模型为E=332.24*(1-Ce/(2937.71+Ce))；以ET-1为药效指标时，杜仲中各成分整合后的PK-PD模型为E=251.09*(1-Ce/(2768.15+Ce))；以NO为药效指标时，杜仲中各成分整合后的PK-PD模型为E=90.47*Ce/(3.2E-08+Ce)。然后以SHR主动脉血管内皮细胞（VEC）为细胞模型，从细胞药代动力学的角度，建立杜仲的PK-PD结合模型：以AngⅡ为药效指标时，7个成分的PK-PD模型分别为E=301.55+69.89*(1-Ce/(18.58+Ce))， E=322.79*(1-Ce/(18.88+Ce))，E=304.50*(1-Ce/(9.95+Ce))， E=302.66*(1-Ce/(0.40+Ce))， E=308.05*(1-Ce/(0.061+Ce))，E=316.29*(1-Ce/(0.043+Ce))，E=310.74*(1-Ce/(0.086+Ce))；以NO为药效指标时，7个成分的PK-PD模型分别为E=2.70*Ce/(0.0016+Ce)，E=2.57+5*Ce/(0.00054+Ce)，E=2.70+4.31*Ce/(0.0057+Ce)，E=2.60+4.99*Ce/(0.0000021+Ce)，E=2.76+4.05*Ce/(0.15+Ce)， E=2.60+4.99*Ce/(0.0000033+Ce)， E=2.56+4.99*Ce/(0.00001+Ce)。本研究为杜仲降血压药效物质基础的阐明提供了一定的科学依据。