摘要
目的:建立替米沙坦在胰岛素抵抗大鼠体内的药动学-药效学(PK-PD)结合模型,揭示替米沙坦改善大鼠胰岛素抵抗的时程关系。方法:正常SD大鼠高脂高糖饲料喂养,形成大鼠胰岛素抵抗模型。然后随机分为替米沙坦4mg/(kg.day)、8mg/(kg.day)组和对照组,连续45d灌胃给予替米沙坦。在给药后不同时间点取血测定血药浓度,同时在给药前和给药后第9,18,27,36,45天早上空腹情况下采血测定血糖浓度和胰岛素浓度,计算胰岛素敏感性指数作为定量药效的指标。药物的体内暴露程度和胰岛素敏感指数的关系根据PK-PD结合模型估算。结果:胰岛素抵抗大鼠连续给予替米沙坦后,替米沙坦在体内无明显蓄积现象,首次给药和末次给药的主要药动学参数均无明显变化。胰岛素抵抗大鼠长期连续给药后,大鼠胰岛素浓度有较大幅度的降低而血糖浓度变化不大,胰岛素敏感性指数在给药后有显著性提高。替米沙坦4mg/(kg.day)组AUC50为2886.0ng.day/mL,8mg/(kg.day)组AUC50为3218.9ng.day/mL。结论:替米沙坦对胰岛素抵抗的改善作用是一个长期而缓慢的过程,其改善胰岛素抵抗的作用与AUC间有良好的相关性。
Aim： A multiple-dose pharmacokinetic-pharmacodynamic model was proposed to study the relationship between pharmacokinetic profile and insulin sensitivity index of telmisartan. Methods： Model of insulin-resistance was developed by feeding high-fat and high-fructose diet to SD rats in two successive months. The insulinresistance rats were then randomly divided into telmi＇sartan（4 mg/（kg.day））, telmisartan（8 mg/（kg.day）） and control groups. The insulin-resistance rats received repeated gastric dosing of telmisartan in 45 days. The rat plasma samples were collected at predetermined intervals, and determined for telmisartan blood levels. Meanwhile, rat blood glucose and blood insulin levels were determined before dosing and at days 9, 18, 27, 36, and 45 after dosing. Insulin sensitivity index was used as the quantitative parameter for measuring the efficacy. The relationship of drug exposure to insulin sensitivity index was modeled by the suggested pharmacokinetic-pharmacodynamic model. Results： There was no considerable telmisartan accumulation in the rats after oral multiple-dosing administration. No significant difference in the pharmacokinetic parameters between the first and the final administration was found. AUC50 of insulin sensitivity index at 4 mg/（ kg. day） and 8 mg/（ kg. day） were 2 886.0 ng.day/mL and 3 218.9 ng.day/mL, respectively. Conclusion： Our results indicates that there is a long and slow period in the improvement of telmisartan to insulin resistance and that this effect is well correlated with the drug exposure index instead of drug concentration.
出处
《中国药科大学学报》
CAS
CSCD
北大核心
2008年第5期422-427,共6页
Journal of China Pharmaceutical University
基金
江苏省药物代谢动力学重点实验室资助项目(No.BM2001201)~~
