高原低氧对2型糖尿病患者二甲双胍群体药动学和药效学的影响

Effects of plateau hypoxia on population pharmacokinetics and pharmacodynamics of metformin in patients with Type 2 diabetes

目的:二甲双胍为治疗糖尿病的基础用药,高原低氧环境为影响二甲双胍药动学的重要因素,但尚未有高原低氧环境下2型糖尿病(diabetes mellitus type 2,T2DM)患者二甲双胍药动学参数的报道。本研究探讨高原低氧环境对T2DM患者服用二甲双胍药动学的影响,并对二甲双胍药效及用药安全性进行评估。方法:依据纳入排除标准,共纳入服用二甲双胍片的T2DM患者85例,其中高原组(海拔3800 m)32例,对照组(海拔1500 m)53例,共采集172份血样。建立超高效液相色谱-串联质谱(ultra-performance liquid chromatography/tandem mass spectrometry,UFLCMS/MS)方法测定二甲双胍血药浓度,采用Phoenix NLME软件建立中国T2DM人群二甲双胍的群体药动学模型;并比较2组人群的药效及严重不良反应。结果:群体药动学建模结果表明,高原低氧和年龄是模型建立的主要协变量,高原组和对照组药动学参数分布容积(distribution volume,V)、清除率(clearance,CL)、消除速率常数(elimination rate constant,Ke)、半衰期(half-life,T_(1/2))、药时曲线下面积(areaunderthecurve,AUC)、达峰时间(timetoreach maximum concentration,T_(max))比较差异均有统计学意义(均P<0.05)。与对照组相比较,高原组AUC增加23.5%,T_(max)、T_(1/2)分别延长35.8%和11.7%,CL降低31.9%。药效学结果显示,高原组T2DM患者降糖效果与对照组相近,而高原组乳酸含量高于对照组,高原组服用二甲双胍后乳酸含量增高。结论:高原低氧环境下,T2DM患者体内二甲双胍代谢减慢;降糖效果与平原地区相近,且血糖控制率低;高原T2DM患者发生乳酸性酸中毒的可能性高于平原地区。高原T2DM患者可能需通过延长药物服用间隔时间,加强用药教育,提高患者依从性以达到降糖效果。

Objective: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:1500 m)and control group(n=53,altitude:3800 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(T_(1/2)),area under the curve(AUC),time to reach maximum concentration(T_(max)).Compared with the control group,AUC was increased by 23.5%,T_(max)and T_(1/2)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.Conclusion: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.