液相色谱-质谱串联定量测定裸鼠血浆中的来曲唑: 方法学建立、验证以及药物动力学研究应用

doi:10.5246/jcps.2018.10.068

中国药学(英文版) ›› 2018, Vol. 27 ›› Issue (10): 665-674.DOI: 10.5246/jcps.2018.10.068

• 【研究论文】 • 下一篇

液相色谱-质谱串联定量测定裸鼠血浆中的来曲唑: 方法学建立、验证以及药物动力学研究应用

薛钧升², 姚庆宇², 李健², 陈文君², 苏红², 田秀云³, 郝纯毅³, 周田彦^1,2*

1. 北京大学医学部药学院天然药物及仿生药物国家重点实验室, 北京 100191
2. 北京大学医学部药学院药剂学系, 北京 100191
3. 北京大学肿瘤医院肝胆胰外二科北京大学肿瘤医院恶性肿瘤发病机制及转化研究教育部/北京市重点实验室, 北京 100142

收稿日期:2018-05-15 修回日期:2018-07-20 出版日期:2018-10-30 发布日期:2018-09-13
通讯作者: Tel.: +86-010-82801717, E-mail: tianyanzhou@bjmu.edu.cn
基金资助:
National Natural Science Foundation of China (Grant No. 81673500) and Innovation Team of Ministry of Education (Grant No. BMU2017TD003).

Development and validation of a sensitive LC/MS-MS method for the determination of letrozole in nude mice plasma and its application to a pharmacokinetic study

Junsheng Xue², Qingyu Yao², Jian Li², Wenjun Chen², Hong Su², Xiuyun Tian³, Chunyi Hao³, Tianyan Zhou^1,2*

1. Beijing Key Laboratory of molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
2. Department of Pharmaceutics, School of Pharmaceutical Science, Peking University Health Science Center, Beijing 100191, China
3. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing 100142, China

Received:2018-05-15 Revised:2018-07-20 Online:2018-10-30 Published:2018-09-13
Contact: Tel.: +86-010-82801717, E-mail: tianyanzhou@bjmu.edu.cn
Supported by:
National Natural Science Foundation of China (Grant No. 81673500) and Innovation Team of Ministry of Education (Grant No. BMU2017TD003).

摘要/Abstract

摘要：

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, 5 μm), 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2 mg/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。

关键词: 液质联用, 来曲唑, 裸鼠, 药物动力学

Abstract:

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-C₁₈column (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.

Key words: LC-MS/MS, Letrozole, Nude mice, Pharmacokinetics

中图分类号:

R943

Supporting:

薛钧升, 姚庆宇, 李健, 陈文君, 苏红, 田秀云, 郝纯毅, 周田彦. 液相色谱-质谱串联定量测定裸鼠血浆中的来曲唑: 方法学建立、验证以及药物动力学研究应用[J]. 中国药学(英文版), 2018, 27(10): 665-674.

Junsheng Xue, Qingyu Yao, Jian Li, Wenjun Chen, Hong Su, Xiuyun Tian, Chunyi Hao, Tianyan Zhou. Development and validation of a sensitive LC/MS-MS method for the determination of letrozole in nude mice plasma and its application to a pharmacokinetic study[J]. Journal of Chinese Pharmaceutical Sciences, 2018, 27(10): 665-674.

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液相色谱-质谱串联定量测定裸鼠血浆中的来曲唑: 方法学建立、验证以及药物动力学研究应用

Development and validation of a sensitive LC/MS-MS method for the determination of letrozole in nude mice plasma and its application to a pharmacokinetic study

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