Effect Of Simulated High Altitude Hypoxia On Pharmacokinetics Of Metformin Hydrochloride And Acetaminophen

Objective:To investigate the pharmacokinetics of metformin hydrochloride and acetaminophen,and the expression changes of organic cation transporters 2?OCT2?as renal clearance-related drug transporter of metformin hydrochloride and uridine diphosphate glucuronosyltransferase 1A1?UGT1A1?as drug metabolic enzyme of acetaminophen in rats under simulated high altitude hypoxia.The project provided the theoretical evidence to clinical rational use of metformin hydrochloride and acetaminophen in high altitude hypoxia environment.Methods:The SD rats?Xi'an City,Shanxi Province?were divided into two groups:metformin hydrochloride group and acetaminophen group.Each group was randomly divided into three groups,namely,control group?Xi'an City,Shanxi Province,400 m,PaO₂:20 kPa?,acute hypoxia group?Xining City,Qinghai Province,kept in a hypobaric oxygen chamber for 3 days,5000 m,PaO₂:11.1 kPa?and chronic hypoxia group?Xining City,Qinghai Province,kept in a hypobaric oxygen chamber for 30 days,5000 m,PaO₂:11.1 kPa?.Serial blood samples were collected from fundus veins into heparinized tubes before?baseline?and at 10 min,30 min,1 h,1.5 h,2 h,3 h,4 h,6 h,8 h and 12 h after the drug administration.Metformin hydrochloride and acetaminophen in plasma were determined by HPLC.Non-compartmental analysis using DAS 2.0 software was performed to calculate pharmacokinetic values of each group.The change of physiological indexes such as O₂ saturation of capillary blood?ScO₂?,granulocyte?Gra?,red blood cell?RBC?,mean corpuscular volume?MCV?,hemoglobin?HGB?,total bilirubin?TB?,total cholesterol?TC?,white blood cell?WBC?,albumin?ALB?and glucose?GLU?in each group were measured.The protein and mRNA expression of OCT2 and UGT1A1 were determined by ELISA and qPCR in rats,respectively.Results:Compared with the control group,the value of ScO₂ were decreased by15.6%and 13.1%,the RBC were increased by 30.2%and 9.3%in acute hypoxia group and chronic hypoxia group.The value of Gra increased by 59.7%,MCV decreased by 8.5%in acute hypoxia group,than that of control group.The value of HGB,TB and TC of chronic hypoxia group increased by 10.3%,34.6%and 33.3%,respectively,compared with control group.The value of WBC,ALB and GLO of chronic hypoxia group decreased by 32.2%,8.2%and 25.3%,respectively,than that of control group.We found statistically significant differences in pharmacokinetic parameters of metformin hydrochloride and acetaminophen when comparing the control group with acute hypoxia group or chronic hypoxia group.The study showed that the t1/2 of metformin hydrochloride increased by 27.8%and 56.6%,respectively,in acute hypoxia group and chronic hypoxia group.Compare with the control group,the MRT_0-t of acute hypoxia group and chronic hypoxia increased by 24.6%and 53.6%,respectively.The ke of two hypoxia groups decreased by 22.9%and 37.1%,respectively,than that in the control group.There was no significant change in the C_max between the control group and the acute hypoxia group,however,the C_maxax dropped by 25.6%in the chronic hypoxia group,than that of control group.Compared with the control group,the t_1/2 of acetaminophen increased by 21.7%and40.9%,the MRT_0-t increased by 19.6%and 24.6%,respectively,in acute hypoxia group and chronic hypoxia group.The AUC_0-t increased by 95.5%and 133.4%,the AUC_0-?increased by 91.9%and 133.90%,respectively,in acute hypoxia group and chronic hypoxia group.The Cmax of acute hypoxia group and chronic hypoxia group was 76.8%and 93.7%higher than that in the control group.Compared with the control group,the CL decreased by 48.1%and 56.9%,the V_d decreased by 37.6%and38.7%,the ke decreased by 14.7%and 29.4%,respectively,in acute hypoxia group and chronic hypoxia group.The study suggested that simulated high altitude hypoxia could cause significant decreases in the protein and mRNA expression for rat OCT2 and UGT1A1 in vivo.The protein expression of OCT2 was 31.1%lower in acute hypoxia group,than in the control group.Compared with the control group,the expression of OCT2 protein in chronic hypoxia group did not change but showed decreased trend.There was no significant difference in the mRNA expression of OCT2 in acute hypoxia group and chronic hypoxia group,but there was a tendency to decrease.The protein expression of UGT1A1 was significantly lower by 38.9%and 24.7%in the acute hypoxia group and the chronic hypoxia group,respectively,than in control group.Compared with control group,the mRNA expression of UGT1A1 in the chronic hypoxia group decreased by 42.0%,the mRNA expression of UGT1A1 in the acute hypoxia group did not change significantly,but there was a tendency to decrease.Conclusion:Simulated high altitude hypoxia had a significant effect on the pharmacokinetic characteristics of metformin hydrochloride and acetaminophen in rats,which was reflected by prolonged t_1/2 and MRT,increased AUC and C_max,and decreased CL and ke.The mechanism may be related to the decreased expression of OCT2 and UGT1A1 under the high altitude hypoxia environment.There are many factors affecting drug metabolism in high altitude hypoxic,and the mechanism of the effects of high altitude hypoxia on the pharmacokinetic characteristics of metformin hydrochloride and acetaminophen remains to be further studied.