Effect Of High Altitude Hypoxia On Pharmacokinetics Of Losartan Potassium

Objective:To investigate the pharmacokinetics changes of losartan potassium and its metabolite losartan carboxylic acid（EXP 3174）in rats under hypoxic environment,and the effect of high altitude hypoxic environment on the metabolic enzyme CYP2C11.This project provides theoretical guidance for the clinical rational use of losartan potassium in high altitude hypoxic environment.Methods:The SD male rats were divided into 4 groups,namely,normoxia group（P,Xi’an,390 m）,acute hypoxia group（AH,plain rats were transported to Maduo and reared for 3 days,4 300 m）,chronic hypoxia group（CH,plain rats were transported to Maduo and reared for 30 days,4 300 m）,and chronic hypoxia return to normoxia group（CH-P,plain rats were transported to Maduo for 30 days and then returned to Xi’an for7 days）.After modeling,the rats in each group were collected blood from the abdominal cardinal vein to measure physiological and biochemical parameters such as white blood cells（WBC）,hemoglobin（HGB）,red blood cells（RBC）,hematocrit（HCT）,mean corpuscular volume（MCV）,platelet number（PLT）,mean platelet volume（MPV）,alanine aminotransferase（ALT）,aspartate Transaminase（AST）,Total Protein（TP）,Albumin（ALB）,Globulin（GLO）,Urea,Glucose（GLU）,Triglyceride（TG）,and Cholesterol（TC）.Hematoxylin-eosin staining method was used to observe the morphological changes of heart,lung,liver and kidney tissues.Blood samples were collected from fundus veins at 0.083,0.25,0.5,1,2,3,4,6,8,12,and 24 h after a single intragastric administration.UHPLC-MS was used to determine the plasma concentration of losartan potassium and its main metabolite EXP 3174,and their pharmacokinetic parameters were calculated.Western blot and q PCR were used to assess the protein and m RNA expressions of CYP2C11 in rats.Results:Compared with Group P,the blood routine and biochemical indexes of the rats in other groups changed significantly,mainly manifested as the increasing of HGB,ALB,GLU and the decreasing of HCT,MCV,MPV,ALT,AST,TP,GLO and TC.In addition,compared with Group P,the value of RBC and WBC were increased while UREA and TG were decreased in Group AH.In Group CH,the value of RBC increased,and UREA,TG and PLT decreased.In Group CH-P,the value of TG increased and RBC decreased.The results of HE staining showed that high altitude hypoxic environment had certain effects on the heart,kidney,liver and lung tissues of rats,while no substantial damage was found.The pharmacokinetics of losartan potassium and EXP 3174 changed significantly at high altitude hypoxia.Compared with Group P of losartan potassium,the AUC_0-tdecreased by 40.13%and 54.49%,the MRT_0-t decreased by 10.20%and 15.00%,the C_max decreased by 57.18%and 58.56%,the t_1/2 decreased by 17.53%and 21.65%,the k_e increased by 20.83%and 29.17%,the V_d increased by 21.54%and 58.85%,and the CL increased by 43.75%and 87.50%in Group AH and Group CH of losartan potassium.In Group CH-P of losartan potassium,the t_1/2 increased by 44.33%,and the k_e decreased by 25.00%than that in Group P.Compared with Group P of EXP 3174,the AUC_0-tdecreased by 43.32%and 53.94%,the MRT_0-t decreased by 19.14%and 20.22%,the C_max decreased by 37.62%and 45.31%,and the CL increased by 57.02%and 101.65%in Group AH and Group CH of EXP 3174.There was no significant change in the CL,V_d and k_e between Group P and Group CH-P.However,the t_1/2 prolonged by 38.28%in Group CH-P than that of Group P of EXP 3174.The protein and m RNA expression of CYP2C11 in rat liver changed in hypoxic environment.The m RNA expression of CYP2C11 in Group AH was considerably higher by 40.32%as compared to Group P.In Group CH,the protein and m RNA expressions of CYP2C11 rose by 34.79%and 53.64%,respectively.There were no significant changes in the expression of protein or gene in Group CH-P.Conclusion:The metabolism of losartan potassium in rats was accelerated at high altitude,mainly manifested in the decrease of t_1/2 and the increase of CL.The mechanism may be related to the increased expression of drug metabolizing enzyme CYP2C11 in hypoxic environment.