Effects of plateau hypoxia on population pharmacokinetics and pharmacodynamics of metformin in patients with Type 2 diabetes.
10.11817/j.issn.1672-7347.2023.220267
- Author:
Yike SHEN
1
;
Xiaohong LUO
2
;
Ningning QIN
3
;
Lin HU
3
;
Lin LUO
3
;
Zhen WANG
4
;
Yuemei SUN
3
;
Rong WANG
5
;
Wenbin LI
3
Author Information
1. Department of Pharmacy, 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, Lanzhou 730020. shenyk19@lzu.edu.cn.
2. Department of Endocrinology, 940th Hospital of Joint Logistics Support force of Chinese People's Liberation Army, Lanzhou 730050.
3. Department of Pharmacy, 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, Lanzhou 730020.
4. Department of Internal Medicine, Yushu Bayi Hospital, Yushu Qinghai 815000, China.
5. Department of Pharmacy, 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, Lanzhou 730020. wangrong-69@163.com.
- Publication Type:Journal Article
- Keywords:
Type 2 diabetes mellitus;
lactic acid;
metformin;
pharmacokinetic parameters;
plateau hypoxia;
rational drug use
- MeSH:
Humans;
Diabetes Mellitus, Type 2/drug therapy*;
Metformin/therapeutic use*;
Acidosis, Lactic;
Tandem Mass Spectrometry;
Hypoxia;
Glucose
- From:
Journal of Central South University(Medical Sciences)
2023;48(4):481-490
- CountryChina
- Language:English
-
Abstract:
OBJECTIVES:Metformin is the basic drug for treating diabetes, and the plateau hypoxic environment is an important factor affecting the pharmacokinetics of metformin, but there have been no reports of metformin pharmacokinetic parameters in patients with diabetes mellitus type 2 (T2DM) in the high-altitude hypoxic environment. This study aims to investigate the effect of the hypoxic environment on the pharmacokinetics and assess the efficacy and safety of metformin administration in patients with Type 2 diabetes mellitus (T2DM).
METHODS:A total of 85 patients with T2DM taking metformin tablets in the plateau group (n=32, altitude: 1 500 m) and control group (n=53, altitude: 3 800 m) were enrolled according to the inclusion and exclusion criteria, and 172 blood samples were collected in the plateau group and the control Group. A ultra-performance liquid chromatography/tandem mass spectrometry (UFLC-MS/MS) method was established to determine the blood concentration of metformin, and Phoenix NLME software was used to establish a model of pharmacokinetics of metformin in the Chinese T2DM population. The efficacy and serious adverse effects of metformin were compared between the 2 groups.
RESULTS:The population pharmacokinetic modeling results showed that plateau hypoxia and age were the main covariates for model building, and the pharmacokinetic parameters were significantly different between the plateau and control groups (all P<0.05), including distribution volume (V), clearance (CL), elimination rate constant (Ke), half-life(T1/2), area under the curve (AUC), time to reach maximum concentration (Tmax). Compared with the control group, AUC was increased by 23.5%, Tmax and T1/2 were prolonged by 35.8% and 11.7%, respectively, and CL was decreased by 31.9% in the plateau group. The pharmacodynamic results showed that the hypoglycaemic effect of T2DM patients in the plateau group was similar to that in the control group, the concentration of lactic acid was higher in the plateau group than that in the control group, and the risk of lactic acidosis was increased after taking metformin in the plateau population.
CONCLUSIONS:Metformin metabolism is slowed down in T2DM patients in the hypoxic environment of the plateau; the glucose-lowering effect of the plateau is similar, and the attainment rate is low, the possibility of having serious adverse effects of lactic acidosis is higher in T2DM patients on the plateau than on the control one. It is probably suggested that patients with T2DM on the plateau can achieve glucose lowering effect by extending the interval between medication doses and enhancing medication education to improve patient compliance.
