摘要
A sensitive,rapid and simple liquid chromatography-tandem mass spectrometric（LC-MS/MS） method was developed and validated for the determination of letrozole（LTZ） in nude mouse plasma in the current study,which was successfully applied to a pharmacokinetic study.Using anastrozole as internal standard（IS）,plasma samples went through a one-step protein precipitation with acetonitrile before determination.The analyte and IS were analyzed on a reversed-phase ZORBAX-SB-C18 column（4.6 mm×250 mm,5 μm） with an isocratic mobile phase consisting of acetonitrile and water containing 0.1% formic acid（v/v） at a flow rate of 1.0 mL/min.The analyte and IS were detected by a triple-quadrupole tandem mass spectrometer,and electrospray and multiple reaction monitoring（MRM） were employed to select LTZ at m/z 286.4/217.1 and IS at m/z 294.1/225.3 simultaneously in the positive ion mode.The calibration curve showed good linearity ranging from 0.8–2000.0 ng/mL（r〉0.99）.The intra-day and inter-day precisions of LTZ were 4.0%–8.4%,with an accuracy of 98.6%–104.9%.Using this method,we successfully characterized the pharmacokinetics（PK） of LTZ by a one-compartment model with first-order absorption in female BALB/c nude mice.
本研究成功建立了一种灵敏、快速且简单的液相色谱-质谱串联方法,用以测定裸鼠血浆中来曲唑的药物浓度,并将其应用于药物动力学研究。以阿那曲唑作为内标,血浆样本经过一步乙腈沉淀蛋白前处理后进行分析测定。采用C18反相柱(4.6 mm×250 mm,5μm),乙腈–0.1%甲酸水溶液(60:40,v/v)为流动相组分,流速1.0 mL/min,以完成色谱分离过程。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来曲唑和阿那曲唑同时进行质谱检测。标准曲线在0.8–2000 ng/mL浓度范围内呈现良好线性(r>0.99)。该方法定量下限可达0.8 ng/mL,且日间、日内准确度、精密度均处于可接受范围。该方法成功应用于雌性BALB/c裸鼠单次口服来曲唑2mg/kg的临床前药物动力学研究,并建立一级吸收的一室模型以描述其药物动力学行为。
基金
National Natural Science Foundation of China(Grant No.81673500)
Innovation Team of Ministry of Education(Grant No.BMU2017TD003)
