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目的:建立药动学-药效学结合模型分析蝙蝠葛碱在犬体内药动学与其对心电图影响之间的关系。方法:蝙蝠葛碱6 mg·kg-1静脉注射后,8 h内定时取血,同时观察并记录心电图变化。采用反相高效液相-紫外法测定血浆中蝙蝠葛碱的浓度。应用3P97程序药动-药效参数估算程序对血药浓度和效应时间数据进行估算。结果:蝙蝠葛碱在犬体内动力学行为符合二房室开放模型,t1/2α=0.049±0.016 h;t1/2β=2.7±0.6 h。蝙蝠葛碱对HR的最大抑制率为(26.4±6.1)％,对PR,QRS,和Q-Tc间期的最大延长率分别为(33.7±10.0)％、(35.6±12.0)％和(25.5±9.4)％。效应滞后于血药浓度10~15 min。药理效应与效应室浓度之间的关系符合sigmoid-Emax模型。结论:以上模型很好地描述了蝙蝠葛碱在犬体内的血药浓度与其对心电图的药理效应之间的关系。
OBJECTIVE: To establish a pharmacokinetic-pharmacodynamic combination model for the analysis of the relationship between the pharmacokinetics of dauricine in dogs and its effect on electrocardiogram. METHODS: After intravenous injection of dauricine 6 mg·kg-1, blood was taken within 8 h, and ECG changes were observed and recorded. The concentration of dauricine in plasma was determined by RP-HPLC. The plasma drug concentration and effect time data were estimated using the 3P97 program pharmacokinetic-pharmacological parameters estimation program. RESULTS: The dynamic behavior of dauricine in dogs was consistent with a two-compartment open model, t1/2α=0.049±0.016 h; t1/2β=2.7±0.6 h. The maximal inhibition rate of dauricine on HR was (26.4±6.1)%, and the maximum prolongation rates for PR, QRS, and Q-Tc intervals were (33.7±10.0)%, (35.6±12.0)%, and (25.5). ±9.4)%. The effect lags behind the plasma concentration 10-15 min. The relationship between pharmacological effects and effector chamber concentration was consistent with the sigmoid-Emax model. Conclusion: The above model describes the relationship between the plasma concentration of dauricine in dogs and its pharmacological effects on electrocardiogram.