目的 建立LC-MS/MS方法研究高原低氧環(huán)境下鹽酸二甲雙胍在2型糖尿?。═2DM）大鼠體內(nèi)的藥動學(xué)特征，并與正常大鼠體內(nèi)的藥動學(xué)特征進(jìn)行差異分析。方法 高糖高脂飼料喂養(yǎng)合并ip鏈脲佐菌素（STZ）制備T2DM大鼠模型；采用Gemini C18（75 mm×3 mm，3μm）色譜柱分離，乙腈-水-甲酸（85：15：0.1）為流動相等度洗脫，質(zhì)譜正離子多反應(yīng)模式下定性定量分析；T2DM大鼠與正常大鼠分別單次ig給予二甲雙胍后，采集血樣，測定血漿藥物濃度，采用DAS2.0藥動學(xué)軟件計算藥動學(xué)參數(shù)。結(jié)果 二甲雙胍質(zhì)量濃度在25~16 000 ng·mL^-1內(nèi)線性關(guān)系良好（r=0.999 2），定量下限為25 ng·mL^-1；大鼠單次ig二甲雙胍后，與正常大鼠組相比，T2DM大鼠二甲雙胍藥時曲線下面積（AUC）增加了25.15%，峰濃度（C_max）增加了28.28%，清除率（CL_z/F）減小了20.00%（P<0.05）。結(jié)論 高原低氧環(huán)境下，與正常大鼠相比，二甲雙胍在T2DM模型大鼠體內(nèi)的AUC、C_max、CL_z/F變化具有顯著性差異。

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

國家自然科學(xué)基金資助項目（82173738）