基于药动学与药效学相关联的养阴通脑颗粒主要有效部位正交配伍研究

Orthogonal compatibility study on main effective parts of Yangyin Tongnao Granules based on pharmacokinetics and pharmacodynamics

目的探讨养阴通脑颗粒主要有效部位(总生物碱、总黄酮、总皂苷、总酚酸)配伍后在脑缺血再灌注模型大鼠体内药物浓度及其药动学与药效学变化。方法采用正交试验法组成上述主要有效部位用量配比不同的9个组方,供脑缺血再灌注模型大鼠ig给药,高效液相色谱-二极管阵列检测器(HPLC-DAD)测定不同时间点血浆中的葛根素、阿魏酸和川芎嗪血浆药物浓度。DAS 3.2.6软件以非房室模型拟合药动学参数,并运用总量统计矩法和综合评分法对整体药动学特征进行评价。同时采用酶联免疫吸附测定(ELISA)法测定大鼠血浆中超氧化物歧化酶(SOD)和过氧化氢酶(CAT)的含量。最后进行药动学-药效学(PK-PD)模型研究,获得各药物浓度与药效之间的定量方程。结果葛根素、阿魏酸和川芎嗪在模型大鼠体内的药动学特征有所差异。总量统计矩和综合评分研究表明不同配伍对总量零阶矩、总量平均滞留时间、综合评分等参数影响不一。主要有效部位正交配伍给药后,一定程度上会抑制脑缺血再灌注大鼠血浆中SOD和CAT的降低。各PK-PD模型均采用Sigmoid-Emax模型,拟合结果与实测数据之间相关性良好,R值均大于0.85。结论养阴通脑颗粒主要有效部位配伍对模型大鼠体内的药动学行为和抗氧化指标具有一定影响;中药复方多成分药物代谢动力学可采用总量统计矩和综合评分法进行研究;PK-PD结合模型可用于中药复方多成分药动学与药效学之间相关性的评价与预测。

Objective To investigate the pharmacokinetic and pharmacodynamic changes of Yangyin Tongnao Granules(YTG)in cerebral ischemia reperfusion rats after the compatibility of main effective parts(total alkaloids,total flavonoids,total saponins and total phenolic acids).Methods By using the orthogonal design to research the main effective parts of YTG,nine different dosage ratios combinations were formed,which were used for oral administration in cerebral ischemia reperfusion rats.High performance liquid chromatography-diode array detector(HPLC-DAD)was used to determine the concentration of puerarin,ferulic acid,and ligustrazine in rat plasma at different time points.The non-compartmental model was used to fit the pharmacokinetic parameters by Drug and Statistics(DAS)3.2.6 software.The total quantum statistical moment analysis method and comprehensive evaluation method were used to evaluate the total pharmacokinetic characteristics.Meanwhile,the content of superoxide dismutase(SOD)and catalase(CAT)were determined by enzyme-linked immunosorbent assay(ELISA)kits.Finally,the PK-PD model and the quantitative equations between drug concentration and efficacy were obtained.Results The pharmacokinetic characteristics of puerarin,ferulic acid and ligustrazine in cerebral ischemia-reperfusion rats were different.Total statistical moment and comprehensive score study showed that different combinations had different effects on ACUT,mean retention time(MRT),and comprehensive evaluation.The effective parts inhibited the reduction of oxidation indexes such as SOD and CAT.Sigmoid-Emax models were adopted in all PK-PD models,and the fitting results had a good correlation with the measured data.The R values were more than 0.85.Conclusion Compatibility of YTG activity parts had a certain effect on their pharmacokinetic behaviors and antioxidation in model rats.The total quantum statistical moment analysis and comprehensive evaluation method can be used to study the pharmacokinetics of multi-component traditional Chinese medicine prescriptions.PK-PD model could be used to predict and evaluate the correlation between pharmacokinetics and pharmacodynamics of traditional Chinese medicine prescriptions.