A liquid chromatography-tandem mass spectrometric method for the determination of axitinib in nude mouse plasma: development, validation and application to a pharmacokinetic study  

裸鼠血浆内阿西替尼的液相色谱–串联质谱测定法:建立、验证及在药物动力学研究中的应用（英文）

作　　者：马元亨 李健[1] 苏清虹 陈文君[1] 卢炜[1,2] 周田彦[1,2] 

机构地区：[1]北京大学医学部药学院分子药剂学与新释药系统北京市重点实验室,北京100191 [2]北京大学医学部天然药物及仿生药物国家重点实验室,北京100191

出　　处：《Journal of Chinese Pharmaceutical Sciences》2016年第5期342-350,共9页中国药学（英文版）

基　　金：National Natural Science Foundation of China(NSFC,Grant No.81473277)

摘　　要：In the present study, a simple, rapid, and sensitive liquid chromatography-tandem mass spectrometric method for the determination of axitinib in nude mouse plasma was developed, validated, and applied to a pharmacokinetic study. Plasma samples were pre-treated by protein precipitation with acetonitrile spiked with erlotinib as an internal standard. The chromatographic separation was accomplished by using a reversed phase C18 column （50 mm×2 mm, 5 μm） with a simple mobile phase system composed of methanol and water （60：40, v/v） at an isocratic flow rate of 0.4 mL/min. The analyte was detected by a triple-quadrupole tandem mass spectrometer via electrospray ionization and multiple reaction monitoring was employed to select both axitinib and erlotinib in the positive ion mode. The calibration curves were linear （r〉0.99） ranging from 1 to 1000 ng/mL, and the lowest level of this range was the lower limit of quantification. The intra- and inter-day precision were 7.7%-12.0%, and the accuracies ranged from 88.6% to 110.4%. This method was successfully applied to a preclinical pharmacokinetic study on female nu/nu nude mice administrated with a single oral dose of axitinib at 120 mg/kg, and the pharmacokinetics was characterized by a one-compartment model with first-order absorption.本研究建立并验证了一种简单、快速且灵敏的液质联用方法,用于测定裸鼠血浆中阿西替尼的浓度,并将其应用于药物动力学实验。血浆样品采用含有内标物埃罗替尼的乙腈进行蛋白沉淀处理。色谱分离过程使用C18反相色谱柱(50 mm×2 mm,5μm),以简单溶剂系统甲醇–水(60:40,v/v)作流动相,流速0.4 mL/min。质谱检测过程使用三重四极杆串联质谱,以电喷雾正离子模式、质谱多反应监测技术对待测物阿西替尼和内标埃罗替尼进行检测。标准曲线的线性范围为1至1000 ng/mL(r>0.99),其最低浓度为定量下限。方法日间日内精密度为7.7%–12.0%,准确度介于88.6%与110.4%之间。该方法成功应用于雌性nu/nu裸鼠口服给予120 mg/kg阿西替尼的临床前药物动力学研究,采用一级吸收一室模型描述其药动学行为。

关 键 词：AXITINIB LC-MS/MS Nude mice PHARMACOKINETICS 

分 类 号：R965[医药卫生—药理学] O657.63[医药卫生—药学]