人血浆中瑞格非尼的LC-MS/MS法测定及其药动学

Determination of Regorafenib in Human Plasma by LC-MS/MS and Its Pharmacokinetics

建立了液相色谱-串联质谱法测定人血浆中的瑞格非尼,并应用于人体药动学研究。采用Dikma C18色谱柱,以2 mmol/L乙酸铵溶液(含0.1%甲酸)∶甲醇(35∶65)为流动相;质谱采用电喷雾电离源(ESI),多反应监测(MRM)模式,监测离子对m/z 483.1→m/z 269.9(瑞格非尼)和m/z 494.1→m/z 393.9(内标,伊马替尼)。人血浆中的瑞格非尼在20~4 000 ng/ml范围内线性关系良好,日内、日间RSD均小于15%。6名健康男性志愿者单剂量口服瑞格非尼片(40 mg)后的主要药动学参数分别为:c_(max)(2 187.6±332.5)ng/ml,t_(1/2)(6.7±2.6)h,AUC_(0→24 h)(13 469.3±1 311.4)h·ng·ml^(-1),AUC_(0→∞)(15 321.5±1 531.5)h·ng·ml^(-1)。

A LC-MS/MS method was established for the determination of regorafenib in human plasma, and was applied in the pharmacokinetics study in human. A Dikma C18 column was used, with the mobile phase of 2 mmol/L ammonium acetate solution （containing 0.1% formic acid） ：methanol （35 ： 65）. A tandem mass spectrometer was used, equipped with electrospray ionization source and in multiple reaction monitoring （MRM） mode, with transitions of m/z 483.1 →m/z 269.9 （regorafenib） and m/z 494.1 →m/z 393.9 （the internal standard, imatinib）. It was linear for regorafenib in the range of 20-4 000 ng/ml. The intra- and inter-day RSDs were less than 15 %. Six healthy male volunteers were administered a single oral dose of regorafenib （40 mg）. The main pharmacokinetic parameters were as follows： Cmax （2 187.6±332.5） ng/ml, tl/2 （6.7±2.6） h, AUCo→24 h （13 469.3±1 311.4） h·ng·ml^-1, AUCo-∞ （15 321.5±1 531.5） h·ng·ml^-1.