基于半房室PK-PD模型的青阳参皂苷抑制癫痫效果研究

Antiepileptic Efficacy of Qingyangshen Saponins Based on Semicompartment Pharmacokinetic-Pharmacodynamic Model

以青阳参皂苷与抗癫痫药物苯巴比妥(PHB)合用对癫痫的抑制作用为例,针对药物效应滞后于药物浓度这一现象进行了深入研究.讨论了常用的药代动力学(PK)模型,得到相应的时间-浓度关系,并以此为基础引入效应室概念,利用半房室模型消除滞后现象,从而建立相应的浓度-效应关系,即药效动力学(PD)模型.以小鼠为实验对象,进行血管外PHB单独给药及PHB、青阳参皂苷混合给药两种方式,并进行最大电惊厥实验,采集0.17~12 h内的血药浓度和小鼠抗惊厥反应数据,建立两种给药方式下的半房室PK-PD模型,根据可决系数R2与均方误差MSE评价模型拟合效果,并计算出相应的PK和PD参数.最后以PHB单独给药方式为参照,利用生物等效性原理评价青阳参皂苷抗癫痫的效果.单独PHB给药下的AUC((0-t))、AUC((0-∞))、C_(max)、T_(max)和T1/2分别为25.96、35.66、3.6 mg/L、1 h和6.187 h,达到最大效应时的效应室浓度大约为8 mg/L,且讨论20%~80%效应时浓度每增加1 mg癫痫抑制的效果就增加14.8%.而将青阳参皂苷和PHB合用后的PK参数分别为32.54、55.9、4.26 mg/L、1 h和9.493 h,达到最大效应时的浓度约为5 mg/L,并且药物抑制癫痫的效应上升到了24.5%.结果表明青阳参皂苷与PHB合用时能有效提高癫痫抑制率.因此,该半房室PK-PD模型为药物的药效定量分析提供了合理的方法手段.

The phenomenon that drug effect lags behind drug concentration was studied,and the inhibitory effect of Qingyangshen saponins in combination with the antiepileptic drug phenobarbital(PHB)on epilepsy was taken as an example.Firstly,the commonly used pharmacokinetic(PK)model was discussed,and the corresponding time-concentration relationship was derived.Based on this,the concept of effect compartment was introduced,and the pharmacodynamic(PD)model was established by using the semicompartment model.The maximum electroconvulsive experiments were conducted by using extravascular administration of PHB alone and a mixture of PHB and Qingyangshen saponins,and the blood concentration and anticonvulsive response data were collected from 0.17 to 12 h.Then the semicompartment PK-PD model under two drug administration methods was established,and the fitting effect of the model was evaluated according to the decidability factor R~2 and mean square error(MSE).The pharmacokinetic and pharmacodynamic parameters were calculated simultaneously for two different drug administration methods.The bioequivalence principle was used to evaluate the antiepileptic effect of Qingyangshen saponins using the PHB alone administration method as a reference.The AUC(0-t),AUC(0-∞),C_(max),T_(max),and T1/2under PHB administration alone were 25.96,35.66,3.6 mg/L,1 h,and 6.187 h,respectively,and the effect compartment concentration at which the maximum effect was reached was approximately 8 mg/L,and the effect of seizure suppression increased by 14.8%for each 1 mg increase in concentration when the 20%to 80%effect was discussed.In contrast,the PK parameters after combining Qingyangshen saponins and PHB were 32.54,55.9,4.26 mg/L,1 h and 9.493 h,respectively,and the concentration at which the maximum effect was reached was approximately 5 mg/L,and the effect of drug suppression of epilepsy rose to 24.5%.The results showed that Qingyangshen saponins can effectively increase the rate of epilepsy inhibition when used in combination with PHB.The semicompartment PK-PD model provides a reasonable method for quantitative analysis of drug efficacy.