厄贝沙坦与氢氯噻嗪联用在肾性高血压大鼠体内药动学-药效学关系研究

目的:应用药动学-药效学结合模型研究厄贝沙坦与氢氯噻嗪联用在肾性高血压大鼠体内单剂量及多剂量用药时的药动学-药效学关系。方法:将SD大鼠制备成2肾1夹型肾性高血压模型,给大鼠单剂量或多剂量灌胃给药,分别于第1天和第8天连续的预定时间点测定血药浓度,同时测定动脉收缩压(SBP)和动脉舒张压(DBP)等药物效应,建立效应室药动学-药效学结合模型并计算相关的药动学和药效学参数。对单用、联用及单剂量、多剂量的药动学-药效学规律进行定量研究。结果:厄贝沙坦的药动学特征呈二室模型,氢氯噻嗪在非稳态和稳态条件下均未改变厄贝沙坦的药动学参数,而在稳态条件下,厄贝沙坦可增高氢氯噻嗪的血药浓度及曲线下面积。厄贝沙坦和氢氯噻嗪联用降压效应优于单用的效应。药物效应和效应室浓度之间符合Sigmoid-Emax药效学模型。单剂量下药物效应与血药浓度间存在滞后现象,多剂量下滞后现象消失。Emax、EC50、Keo等药效学参数在厄贝沙坦组和两药联用组之间的差异有统计学意义。结论:建立了PK-PD定量数学模型研究厄贝沙坦和氢氯噻嗪联用在大鼠体内单剂量和多剂量用药后药动学-药效学(暴露-反应)关系的规律,并提供了相关的药动学和药效学参数,可为临床合理用药提供参考依据。

Pharmacokinetic and pharmacodynamic interaction between irbesartan and hydrochlorothiazide in renal hypertensive rats

AIM: Pharmacokinetic-pharmacodynamic(PK/PD) modeling was applied to investigate the pharmacokinetic and pharmacodynamic interaction between irbesartan and HCTZ in renal hypertensive rats at non-steady-state and steady-state.METHODS: The renal hypertensive rats were treated with oral irbesartan alone,or HCTZ alone,or the combination of irbesartan and HCTZ for 8 days.Systolic and diastolic blood pressure and plasma concentrations were measured after single-and multi-dosing and PK/PD parameters were analyzed.RESULTS:Irbesartan showed a two-compartment model pharmacokinetic profile.The concentration-time course of irbesartan was not changed by HCTZ,but irbesartan increased the peak plasma concentration and area under the curve of HCTZ at steady-state.Irbesartan plus HCTZ had greater blood pressure lowering action than irbesartan alone.HCTZ increased actions of irbesartan.Hysteresis phenomenon was found between effect and plasma concentrations of irbesartan after a single dose.However,hysteresis phenomenon disappeared at steady state with more rapid realization of maximum concentration and effects.The relationship between effects and effect-compartment concentrations of the drugs was represented by a sigmoid Emax model.CONCLUSION: The results suggest synergistic pharmacodynamic interaction between irbesartan and HCTZ in renal hypertensive rats and some differences of PK/PD properties between irbesartan and irbesartan/HCTZ combinations at non-steady state and steady state.These comparisons are likely to be clinically significant.