目的 建立LC-MS/MS方法研究高原低氧环境下盐酸二甲双胍在2型糖尿病（T2DM）大鼠体内的药动学特征，并与正常大鼠体内的药动学特征进行差异分析。方法 高糖高脂饲料喂养合并ip链脲佐菌素（STZ）制备T2DM大鼠模型；采用Gemini C18（75 mm×3 mm，3μm）色谱柱分离，乙腈-水-甲酸（85：15：0.1）为流动相等度洗脱，质谱正离子多反应模式下定性定量分析；T2DM大鼠与正常大鼠分别单次ig给予二甲双胍后，采集血样，测定血浆药物浓度，采用DAS2.0药动学软件计算药动学参数。结果 二甲双胍质量浓度在25~16 000 ng·mL^-1内线性关系良好（r=0.999 2），定量下限为25 ng·mL^-1；大鼠单次ig二甲双胍后，与正常大鼠组相比，T2DM大鼠二甲双胍药时曲线下面积（AUC）增加了25.15%，峰浓度（C_max）增加了28.28%，清除率（CL_z/F）减小了20.00%（P<0.05）。结论 高原低氧环境下，与正常大鼠相比，二甲双胍在T2DM模型大鼠体内的AUC、C_max、CL_z/F变化具有显著性差异。

Objective To study the pharmacokinetic difference of metformin hydrochloride in type 2 diabetes mellitus(T2DM) rats and normal rats under high-altitude hypoxic condition based on LC-MS/MS.Methods T2DM rat model was established by using high-sugar and high-fat diet combined with intraperitoneal injection of streptozocin(STZ).The metformin was separated with Gemini C18 column(75 mm×3 mm, 3 μm) and using acetonitrile-water-formic acid(85:15:0.1) as mobile phase for isometric elution.Qualitative and quantitative analysis was performed in positive ion multiple reaction mode.After a single intragastric administration of metformin in T2DM rats and normal rats, blood samples were collected, plasm drug concentration were determined by LC-MS/MS, and the pharmacokinetic parameters were calculated by DAS 2.0 pharmacokinetics software.Results The results suggested that the mass concentration of metformin in plasma had a great linear relationship at the range of 25-16 000 ng·mL^-1(r=0.999 2), and the lower limit of quantification was 25 ng·mL^-1.After single administration of metformin, the area of concentration-time curve(AUC) increased by 25.15%, peak concentration(C_max) increased by 28.28% and clearance rate(Cl_z/F)decreased by 20.00% in T2DM group compared with normal group(P<0.05).Conclusion Compared with normal group, the three pharmacokinetic parameters of AUC, C_max and Cl_z/F in T2DM group were significantly different.

R285.51

国家自然科学基金资助项目（82173738）