定量比格犬血浆中去甲文拉法辛LC-MS/MS方法的建立及比格犬血浆中富马酸去甲文拉法辛药代动力学研究

摘要

目的:建立一种快速灵敏的液质联用方法定量比格犬血浆中去甲文拉法辛,并进行比格犬体内富马酸去甲文拉法辛药代动力学研究,同时与琥珀酸去甲文拉法辛比格犬体内药代参数进行对比.方法:样品处理采用叔丁基甲醚进行液液萃取,液相分离采用Agilent Eclipse Plus C18色谱柱(2.1 mm×100 mm,3.5μm),以乙腈-乙酸铵缓冲液(1 mmol/L)(体积比80:20)进行等度洗脱.采用单次给药和多次给药试验进行比格犬体内药代动力学研究.结果:此方法具有良好的线性、精密度、准确度,定量下限(0.5 ng/mL)高于文献报道.液液萃取的样品提取方法简便,液质联用分析时间相对较短(3 min).结论:此方法可成功地应用于比格犬血浆中去甲文拉法辛定量分析.比格犬体内富马酸去甲文拉法辛的药代参数(单次给药和多次绐药试验)与对照品琥珀酸去甲文拉法辛没有明显的统计学差异.%Objective: To establish a highly sensitive liquid chromatography-tandem mass spectrometry (LC-MS/ MS) method for the quantification of O-desmethylvenlafaxine(ODV) in beagle dog plasma and applied to a phar-macokinetic study of desvenlafaxine fumarate (DVF) in beagles, while made a phaimacokinetics comparation with desvenlafaxine succinate(DVS). Methods: Sample pretreatment includes liquid-liquid extraction by adding tert-butyl methyl ether to the plasma sample containing the internal standard. HPLC separations were performed on an Agilent Eclipse Plus C18 column (2.1 mm x 100 mm, 3.3 (xm I.d.). Samples were eluted using a mobile phase composed of acetonitrile and 1 mmol/L ammonium acetate in water (80:20 V/V). Single-time studies and multi-time studies were applicated to pharmacokinetic study. Results: The method has high linearity, precision and accuracy, and a sufficiently low detection limit (0.5 ng/mL) which was lower than the limit of previous reports. The liquid-liquid extraction process was simple and the LC-MS/MS run time is relatively short (3 min). Conclusion: This method was successfully applied to the determination of ODV concentration in beagle plasma. The pharmacokinetic parameters of DVF in beagle plasma (single-time and multiple-time studies) showed no significant differences from those of DVS.