Study On Pharmacokinetic Characteristics And Influential Factors Of Common Hypoglycemic Drugs Under High Altitude Hypoxia Enviroment

The incidence of diabetes is increasing year by year,and with the increase of aging,it is estimated that the number of people suffering from diabetes will reach 650million in 2045.People living on the plateau eat mainly beef and mutton,high-salt and high-calorie foods.Eating habits greatly increase the risk of diabetes.And due to the particularity of the high altitude hypoxic environment,it is difficult to control the blood sugar of diabetic patients in the high altitude area.The study of pharmacokinetics is the basis of rational drug use and provides a theoretical reference for the rational use of drugs for diabetes patients in plateau areas.The research of this group is divided into the following parts:Part 1:Study of Altitude Hypoxia on the Changes of Pharmacokinetic Parameters of Commonly Used Antidiabetic DrugsThe effect of high altitude hypoxia on the changes of the pharmacokinetic parameters of the commonly used hypoglycemic drugs metformin,nateglinide and gliquidone was studied.Wistar rats were randomly divided into plain and plateau group.Metformin,nateglinide,and gliquidone were administered by gavage,blood samples were collected,and the plasma concentrations of the above three drugs were determined by UFLC-MS/MS in the plateau and plain environments,and calculate the corresponding pharmacokinetic parameters.The results showed that Compared with the plain group,metformin AUC（0-t）decreased by 14.9%,MRT（0-∞）increased by 120.2%,t_1/2zincreased by 164.5%in the plateau hypoxic environment;Compared with the plain group,nateglinide AUC increased by 93.9%,CL_z/Fdecreased by 43.2%,C_maxalso increased by 61.4%;compared to the plain group,gliquidone AUC increased by 22.3%,Vz/F decreased by 49.6%,and C_maxincreased by 75.0%.There was no statistical difference in other parameters,indicating that the high altitude hypoxic environment caused changes in the pharmacokinetic parameters of metformin,nateglinide,and gliquidone.Part 2:Study on the expression of CYP3A4 and CYP2C9,the key factors affecting the metabolism of nateglinide and gliquidone under high altitude and hypoxic environmentThe pharmacokinetic parameters of the glucose-lowering drugs nateglinide and gliquidone have changed in high altitude hypoxia environment,and the expression of metabolic enzymes plays an important role in pharmacokinetics.The metabolism of nateglinide and gliquidone requires the participation of CYP3A4 and CYP2C9.This chapter uses Western Blot to determine the expression of metabolic enzymes CYP3A4 and CYP2C9 in plateau and plain environments.The results show that compared with the plain group,the expression of metabolic enzymes CYP3A4decreased by 44.9%in liver tissue under plateau hypoxic environment,while metabolic enzyme was no significant difference in the expression of CYP2C9,which proved that the pharmacokinetic changes of nateglinide and gliquidone are related to the decrease of the expression of metabolic enzyme CYP3A4 under high altitude and hypoxic environment.Part 3:Study on the influencing factors of the changes of metformin pharmacokinetic parameters under high altitude hypoxia environmentIn high altitude areas,diabetic patients mainly use metformin to control blood sugar to stabilize.Studies have shown that the pharmacokinetic parameters of metformin have changed in the high altitude hypoxic environment.Among them,the expression of intestinal flora and transporters are related to the metabolism of metformin.The research of the research team showed that the intestinal flora has changed in the plateau environment.In order to study the changes in the pharmacokinetics of metformin are related to change in intestinal flora and changes in transporter expression under high altitude hypoxic environment.In this chapter,after incubating metformin for 0h,12h,and 24h through in vitro experiments,the concentration of metformin was determined,and its concentration did not change significantly.The results show that the intestinal flora does not directly participate in the metabolic process of metformin drugs.through the establishment of a pseudo-sterile model of the intestinal tract,the pharmacokinetic experiments of the plateau and the plain were carried out.The results showed that Compared with the plain group,AUC of rats in the plateau group decreased by 14.9%,MRT（0-∞）increased by 120.2%,t_1/2zincreased by 164.5%;compared with the plain group In the plain pseudo-sterile group,AUC increased by 79.4%,MRT（0-t）increased by 19.5%,CL_z/Fdecreased by 42.7%,and C_maxincreased by 70.8%;compared with the plateau group,the plateau pseudo-sterile group In group rats,AUC increased by 106.7%,MRT（0-∞）decreased by 58.6%,C_maxincreased by 66.5%,t_1/2zdecreased by 68.3%,CL_z/Fdecreased by 34.9%;plain pseudo-sterile group Compared with the plateau pseudo-sterile group,MRT（0-t）decreased by 21.9%.There was no statistical difference in other parameters.It shows that the changes of metformin metabolism in rats are related to the changes of intestinal flora under high altitude hypoxia.The expression of metformin transporters Oct1 and Oct2 in the plateau and plain groups of rats was determined by Western Blot.The results showed that the expression of Oct1in intestinal tissue increased by 77.4%,and the expression of Oct2 in renal tissue decreased by 54.4%.Therefore,the expression of the transporter Oct1 in the intestinal tissue under high altitude hypoxia environment increases,and the expression of Oct2in the kidney tissue decreases.This proves that the changes in the pharmacokinetic parameters of metformin under high altitude hypoxia are related to changes in intestinal flora and changes in the expression of transporters Oct1 and Oct2,and the change of intestinal flora plays a more important role in the plateau environment.