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.