“药效-靶标-成分-药动”多维关联模式下的如意珍宝丸药效物质基础辨识

Identification of Pharmacodynamic Material Basis of Ruyi Zhenbaowan by Multidimensional Correlation Model of "Pharmacodynamic-target-component-pharmacokinetic"

摘要:

目的 通过整合生物网络邻近度计算与药代动力学表征，辨识如意珍宝丸缓解神经病理性疼痛的效应物质基础。方法 利用Cytoscape 3.8.2软件构建“方药候选靶标-疾病相关基因”相互作用网络，采用Pesca 3.8.0工具计算如意珍宝丸候选靶标在该网络中作用于神经病理性疼痛相关基因的平均最短路径值，用以评价二者之间的网络邻近度，筛选对疾病具有强干预效能的方药候选靶标及其对应的潜在效应成分。于设置的时间点收集灌胃给予如意珍宝丸后的大鼠血浆与脑脊液样品，采用超高效液相色谱-四极杆离子阱质谱法（UPLC-Q-TRAP/MS）定量检测各样品中潜在效应成分的含量，并绘制药-时曲线。采用DAS 2.1.1软件计算各效应成分的药代动力学参数。结果 通过对“方药候选靶标-疾病相关基因”相互作用网络中如意珍宝丸候选靶标与神经病理性疼痛相关基因之间的网络邻近度评价，筛选出雌激素受体1（ESR1）、环磷酸腺苷（cAMP）依赖性蛋白激酶催化亚基α（PRKACA）、蛋白激酶B1（Akt1）等40个对神经病理性疼痛相关基因具有强干预效能的如意珍宝丸候选靶标，及其对应的甘草酸、白桦脂酸等10个潜在效应成分。药代动力学表征结果显示，10个潜在效应成分中，没食子酸、芹菜素-7-O-葡萄糖醛酸苷、芹菜素和甘草酸在血浆与脑脊液中均有较好的吸收、代谢特征，起效时间较长、生物利用度较好。结论 该研究从“药效-靶标-成分-药动”多维关联视角，指出甘草酸、没食子酸、芹菜素-7-O-葡萄糖醛酸苷、芹菜素可能是如意珍宝丸缓解神经病理性疼痛的主要效应物质，可为如意珍宝丸效应物质基础的明晰及其质量标准的制定提供可靠的实验证据。

Abstract:

Objective To identify the pharmacodynamic material basis of Ruyi Zhenbaowan in relieving neuropathic pain by integrating the calculation of biological network proximity and pharmacokinetic characterization.Method The interaction network of "drug candidate target-related gene of disease" was constructed by Cytoscape 3.8.2， and the average shortest path value of each drug putative target acting on neuropathic pain-related genes in this network was calculated by Pesca 3.8.0 tool so as to evaluate the network proximity between them， and screen prescription candidate targets with strong intervention efficiency and their corresponding potential effect components. After that， plasma and cerebrospinal fluid samples were collected from rats after administration of Ruyi Zhenbaowan at set time points， and the contents of potential effect components in samples was quantified by ultra performance liquid chromatography-quadrupole-ion trap mass spectrometry（UPLC-Q-TRAP/MS）， and drug concentration-time curves were plotted， then the pharmacokinetic parameters were calculated by DAS 2.1.1.Result By evaluating the network proximity between candidate targets and neuropathic pain-related genes in the interaction network， a total of 40 putative targets of Ruyi Zhenbaowan with strong intervention effects on neuropathic pain-related genes， such as estrogen receptor 1（ESR1）， cyclic adenosine monophosphate（cAMP）-dependent protein kinase catalytic subunit alpha（PRKACA） and protein kinase B1 （Akt1）， and 10 corresponding potential effect components， such as glycyrrhizic acid and betulinic acid， were obtained. Pharmacokinetic characterization showed that among the 10 potential effect components， gallic acid， apigenin-7-O-glucuronide， glycyrrhizic acid and apigenin were well absorbed and metabolized in plasma and cerebrospinal fluid， with long onset time and good bioavailability.Conclusion From the perspective of efficacy-target-constituent-pharmacokinetic， this study analyzes the main effective materials of Ruyi Zhenbaowan， such as glycyrrhizic acid， gallic acid， apigenin-7-O-glucuronide and apigenin， which have a high exposure in plasma or cerebrospinal fluid and have a strong intervention effect on neuropathic pain. The related results provide reliable experimental evidences for clarifying the material basis and developing quality standards of Ruyi Zhenbaowan.