Effects Of Losartan On Pharmacokinetics And Pharmacodynamics Of Glipizide In Type 2 Diabetic Rats

Objective:To investigate the effect of Losartan(GL)on the pharmacodynamics and ph-armacokinetics of Glipizide(GL)in type 2 diabetic rats,which provides the the o-retical foundation for the joint clinical application of the two drugs.Methods:1.Preparation of type 2 diabetic rat modelAfter one week of adaptive feeding,rats were random Ly divided into two groups:the blank control group(Ctrl)and the diabetes model(T2DM)group.Rats in the blank control group were fed with normal diet,and rats in the diabetes model group were fed with high fat and high sugar diet according to the methods described in the literature to establish the model diabetes model.The proportion of lard: sucrose: cholesterol: yolk powder: general feed=10:10:1:5:74.Feeding for 4 weeks,fasting for 12 hours,intraperitoneal injection of 1% STZ solution.72 hours after intraperitoneal injection,fasting blood glucose was measured for 4 consecutive weeks.Observe and record the changes of mental state,fur luster,activity,diet,drinking water,urination,weight and death number of rats during the experiment.fasting blood glucose(FBG),glycated hemoglobin content(HbAlc),oral glucose tolerance(OGTT),serum triglycerides(TG),total cholesterol(TC),low density lipoprotein(LDL),high density lipoprotein(HDL)and other indicators were measured.2.Pharmacokinetic studyPlasma samples collection: randomLy selected 8 as the blank control group,and the successful model was divided into glipizide group and glipizide combined with losartan group.Each group was administrated by gavage,blank control group and glipizide control group were given glipizide(5 mg/kg),glipizide combined with losartan group were given glipizide(5 mg/kg)and losartan(5 mg/kg).During the experiment,the original feeding mode was continued,the blank control group was fed with normal feed,and the rest groups were fed with high sugar and high fat feed for 4 weeks and 28 days.At the end of the 4th week,0.5mL of blood was collected by carotid artery at 1,2,3,4,5,6,8,10 and 12 hours after administration,and about 0.2 mL of plasma was obtained by centrifugation,and sealed at-20 ? for test.A HPLC-UV method was established for the determination of glipizide in plasma samples.Das3.1.5 software was used to calculate the drug concentration time curve and pharmacokinetic parameters.SPSS13.0 statistical software was used to analyze the pharmacokinetic parameters of three groups of rats.3.Pharmacodynamic studyRandomly selected 8 as the blank control group,and the successful model was divided intothe diabetes model group,glipizide group and glipizide combined with losartan group.Each group was given by gavage,glipizide group was given glipizide(5mg/kg),glipizide combined with losartan group were given glipizide(5 mg/kg)and losartan(5 mg/kg),blank control group and diabetes model control group were given the same amount of saline intraperitoneally.During the experiment,the original feeding mode was continued,the blank control group was fed with normal feed,the other groups were fed with high sugar and high fat feed for 4 weeks and 28 days.The mental state,skin luster,activity,diet,drinking water,urination,body weight and death number of rats were observed and recorded during the experiment.The FBG,HbAlc,OGTT,TG,TC,LDL and HDL of the four groups were measured.Results:1.Preparation of type 2 diabetic rat modelCompared with the Ctrl group,T2 DM group showed the typical symptoms of "three more and one less",that is,drinking more,eating more,urinating more and losing weight significantly.In T2 DM group,the direct indexes of hyperglycemia such as FBG and HbAlc were significantly increased,OGTT was significantly damaged,HDL and TC,TG and LDL were significantly decreased.(P < 0.01).2.Pharmacokinetic studyThe elimination half-life of glipizide in T2 DM rats was significantly longer than that in healthy rats(P < 0.05).In T2 DM rats,compared with Glipizide alone,the Cmax and AUC of glipizide in losartan group increased significantly(P < 0.05),and the Tmax decreased significantly(P < 0.05).3.Pharmacodynamic studyCompared with the symptoms of three more and one less in the model control group rats(ie,drinking more,eating more,polyuria,and significant weight loss),the above conditions in the glipizide group were significantly improved;In addition,FBG,HbAlc,LDL,TC and TG in glipizide group were significantly lower than those in glipizide group(P < 0.01),HDL was significantly higher(P < 0.01);OGTT was significantly improved,and the difference was statistically significant(P < 0.01);Compared with Glipizide group,FBG and HbAlc of glipizide combined with losartan group decreased significantly(P < 0.05).Conclusion:1.Compared with the normal state,the pharmacokinetics of glipizide changed significantly in diabetic pathological state.2.Losartan can significantly improve the blood concentration and bioavailability of glipizide.3.Glipizide can improve the hyperglycemic state of diabetic rats,and losartan combined with glipizide can enhance the hypoglycemic effect of glipizide.The mechanism may be that losartan affects the pharmacokinetic process of glipizide,such as shortening the peak time,increasing the peak concentration,increasing the time under the curve,etc.