厄贝沙坦与氢氯噻嗪联用在大鼠体内剂量优化的定量研究

目的:应用权重配方法及非线性混合效应模型,对厄贝沙坦和氢氯噻嗪在肾性高血压大鼠体内联用的剂量优化进行定量评价。方法:根据权重配方设计,将肾性高血压大鼠分为厄贝沙坦和氢氯噻嗪不同剂量组合的6个用药组,以收缩压和舒张压的变化率作为药效指标。综合建立和应用权重配方模型及非线性混合效应模型分析降压效应,评价两药联用在大鼠体内的降压及交互作用,分析最佳剂量配比,并做确定性实验。对权重配方原法和权重配方群体法的计算结果进行比较。结果:成功建立权重配方模型及其群体模型,联用中组分重要程度为厄贝沙坦大于氢氯噻嗪,厄贝沙坦与氢氯噻嗪存在协同作用,在大鼠体内的最优剂量配比为厄贝沙坦∶氢氯噻嗪=10∶1。权重配方原法和群体法在评价组分重要程度、理论优化组方及剂量优化比例等方面的结论相同,但群体法由于采用个体效应值直接计算,对权重指数等参数的计算更为精确,并提供个体间及个体内变异等信息。结论:综合应用权重配方法及非线性混合效应模型,可定量评价厄贝沙坦和氢氯噻嗪联用在大鼠体内的药物相互作用规律,并提供最佳剂量配比的信息,为临床合理药物联用提供依据。

Drug-drug interaction between irbesartan and hydrochlorothiazide in renal hypertensive rats:A case study of dose optimization

AIM:To quantitatively study the dose optimization of drug-drug interaction of irbesartan and hydrochlorothiazide in renal hypertensive rats using weighted modification model and nonlinear mixed effect model.METHODS: Renal hypertensive rats were randomly divided into six groups with different dose combination according to the experimental design of weighted modification method.The rates of change of systolic and diastolic blood pressures were measured as pharmacodynamic indices.Original and population weighted modification methods were comprehensively used to analyze the experimental data and evaluate the drug-drug interaction and dose optimization of irbesartan/hydrochlorothiazide in rats.The results and characteristics of original and population weighted modification methods were compared.RESULTS:The weighted modification models were built successfully.The optimal combination proportion between these two drugs was 10∶1(irbesartan/hydrochlorothiazide) and the nature of interaction was synergism.The role of irbesartan is more important than that of hydrochlorothiazide when used combinedly.The basic research conclusions of original and population weighted modification methods were the same.However,population weighted modification method can provide more accurate parameters such as weighted index and useful information of inter-and intra-individual variabilities.CONCLUSION: The weighted modification methods can be used to quantitatively evaluate the drug-drug interaction and dose optimization of irbesartan/hydrochlorothiazide in rats.