格列吡嗪和格列本脲对氯沙坦药动学的影响

Effect of Glipizide and Glibenclamide on the Pharmacokinetics of Losartan

关键词:  氯沙坦  格列吡嗪  格列本脲  药动学

Key words:  losartan  glipizide  glibenclamide  pharmacokinetics

摘要:

目的 研究格列吡嗪和格列本脲对氯沙坦在大鼠体内药动学的影响。方法 将15只大鼠随机分成对照组、格列吡嗪组和格列本脲组，分别灌胃给予0.5% CMC、10 mg·kg^-1格列吡嗪和10 mg·kg^-1格列本脲，0.5 h后灌胃给予5 mg·kg^-1氯沙坦钾，经尾静脉予不同时间点采集血样，采用HPLC测定血样中氯沙坦及其代谢产物E-3174的浓度。采用DAS计算各组主要的药动学参数，并进行统计学分析。结果 合用格列吡嗪后，氯沙坦和E-3174的AUC、MRT和峰浓度均明显增加，氯沙坦的清除率减小；合用格列本脲后，氯沙坦的达峰时间提前，E-3174的MRT延长。结论 与同剂量的格列本脲相比，格列吡嗪对氯沙坦及其代谢产物在大鼠体内的药动学影响较大。临床上合用氯沙坦和格列吡嗪时，应注意潜在的药物相互作用所致的药物不良反应。

Abstract:

OBJECTIVE To study the effect of glipizide and glibenclamide on the pharmacokinetics of losartan in rats. METHODS Fifteen rats were randomly divided into 3 groups(control group, glipizide group and glibenclamide group) and administrated orally with 0.5%CMC, 10 mg·kg^-1 glipizide and 10 mg·kg^-1 glibenclamide, respectively. The 5 mg·kg^-1 losartan potassium was administrated orally to the rats 0.5 h later and blood samples were collected via tail vein at different time point, which were further processed and analyzed for the concentration of losartan and E-3174 by HPLC. The pharmacokinetic parameters were calculated by DAS, followed by statistical analysis. RESULTS When co-administrated with glipizide, the AUC, MRT and C_max of losartan and E-3174 were significantly increased and the clearance of losartan was significantly decreased; when co-administrated with glibenclamide, only the T_max of losartan and MRT of E-3174 were altered. CONCLUSION Glipizide significantly affected the pharmacokinetics of losartan and its metabolite E-3174 in rats. In clinic, when these two drugs are co-administrated, drug adverse reaction of losartan induced by drug-drug interaction should be paid attention to.