生脉注射液中人参皂苷Rg_1,Rb_1在心肌缺血大鼠体内的药动学-药效学结合研究

Study on PK-PD characteristics of ginsenoside Rg_1 and Rb_1 in rats with myocardial ischemia following intravenous administration of Shengmai injection

该文研究生脉注射液中主要成分人参皂苷Rg1和Rb1在心肌缺血大鼠体内的药动学过程及其诱导体内NO释放效应的药动学-药效学(PK-PD)结合模型。以大鼠皮下注射异丙肾上腺素(ISO)制备心肌缺血模型。模型大鼠静脉给予生脉注射液(10.8 mL·kg-1),于给药后不同时间点采集大鼠血清,测定血清中人参皂苷Rg1和Rb1的浓度,绘制药-时曲线,拟合药动学模型,计算药动学参数;同时测定血清中NO代谢产物NO2-和NO3-水平,绘制时-效曲线,采用Sheiner等提出的效应室理论建立PK-PD结合模型,计算药效学参数。研究结果显示人参皂苷Rg1和Rb1在大鼠体内的药动学过程均符合二房室开放模型,人参皂苷Rg1在体内表现出快消除的特点,人参皂苷Rb1表现出慢消除的特点。生脉注射液诱导大鼠体内NO释放效应与人参皂苷Rg1和Rb1的血药浓度不直接相关,效应滞后于血药浓度,效应与人参皂苷Rg1和Rb1的效应室浓度成良好的相关性,符合Sigmoid-Emax模型。该研究成功建立了生脉注射液在心肌缺血大鼠体内的PK-PD结合模型,可较有效地用于预测生脉注射液的血药浓度和效应。

It is the objective of this paper to study pharmacokinetics-pharmacodynamics（PK-PD）characteristics of ginsenoside Rg1 and Rb1 on the effect of inducing nitric oxide（NO）release after intravenous administration of Shengmai injection to rats with myocardial ischemia. The model of myocardial ischemia rats was produced by subcutaneous injection of isoproterenol. The serum samples were collected at different time points after intravenous administration of Shengmai injection to rats with the dose of 10.8 mL·kg-1. The concentrations of ginsenoside Rg1 and Rb1 in serum were determined, and then the concentration-time curves were drawn. Pharmacokinetic parameters of ginsenoside Rg1 and Rb1 were calculated after the construction of pharmacokinetic models. Meanwhile, NO2- and NO3-, the metabolites of NO, in serum were determined, and then the effect-time curve was drawn. The combined PK-PD model was established based on the theory of effect compartment by Sheiner et al. Then pharmacodynamic parameters were calculated. The results indicated that the pharmacokinetics of ginsenoside Rg1 and Rb1 conformed to a two-compartment model. Ginsenoside Rg1 and Rb1 exhibited quick and slow elimination in rats respectively. The effect of Shengmai injection on inducing NO release did not relate directly with and lagged behind the concentrations of ginsenoside Rg1 and Rb1 in serum. The effect exhibited good correlation with ginsenoside Rg1 and Rb1 levels in effect compartment. The relationship between effect and serum concentration fits Sigmoid-Emax model. This study successfully established the combined PK-PD model of ginsenoside Rg1 and Rb1 after intravenous administration of Shengmai injection to rats. The model can efficiently predict the concentration and effect of Shengmai injection in vivo.