蝙蝠葛碱在Beagle犬体内的药动学与其对心电图的影响(英文)

Pharmacokinetics and effect of dauricine on electrocardiogram in Beagle dogs

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6mg·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10～15min.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.

AIM: To establish a pharmacokinetic-pharmacodynamic (PK-PD) model to analyze the relation between the plasma concentration of dauricine and the effect on electrocardiogram ( ECG) in 4 Beagle dogs. METHODS: 8 hours after intravenous administration of 6 mg·kg-1 dauricine, blood was serially sampled and the effect on electrocardiogram was measured. The plasma concentration of dauricine was measured by HPLC-ultravi-olet method. The time courses of plasma concentration and the effects of dauricine were analyzed with 3P97 program and PK-PD parameters estimate program. RESULTS: The plasma concentration-time course followed a 2-compartment open model. The mean distribution half-life (t1/2α) was 0.049±0.016 h and terminal elimination half-life (t1/2β) was 2.7 ±0.6 h. The maximal decrease in heart rate (HR) was (26.4±6.1)%, whereas the maximal increase in PR, QRS, and Q-Tc intervals were (33.7±10.0)%, (35.6±12.0)% and (25.5± 9.4)% , respectively. All peak effects were appeared approximately 10-15 minutes after intravenous administration of dauricine. Effect on electrocardiogram was analyzed by the effect-link sigmoid Emax model. CONCLUSION: The PK-PD model can successfully characterize the relation between the plasma concentrations of dauricine and the effect on electrocardiogram.