液质联用法同时测定埃罗替尼及其活性代谢产物OSI-420在BALB/c裸鼠体内的浓度及其药代动力学研究

doi:10.5246/jcps.2012.04.040

液质联用法同时测定埃罗替尼及其活性代谢产物OSI-420在BALB/c裸鼠体内的浓度及其药代动力学研究

李梦瑶1,2, 吴琼2, 李汉青2, 宁妙然2, 陈烨2, 李良1,2, 周田彦1,2*, 卢炜1,2*

1. 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
2. 北京大学医学部药学院药剂学系, 北京 100191

收稿日期:2012-04-13 修回日期:2012-05-20 出版日期:2012-06-25 发布日期:2012-06-25

A sensitive LC-MS/MS method to determine the concentrations of erlotinib and its active metabolite OSI-420 in BALB/c nude mice plasma simultaneously and its application to a pharmacokinetic study

Meng-Yao Li, Qiong Wu, Han-Qing Li, Miao-Ran Ning, Ye Chen, Liang Li, Tian-Yan Zhou^*, Wei Lu^*

1. State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100191, China
2. Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China

Received:2012-04-13 Revised:2012-05-20 Online:2012-06-25 Published:2012-06-25
Contact: Tian-Yan Zhou*, Wei Lu*

摘要/Abstract

摘要： 本试验建立了一种简单快速灵敏的液质联用方法, 用以同时测定裸鼠血浆内埃罗替尼及其活性代谢物OSI-420的浓度。采用液液萃取法从血浆中提取埃罗替尼, OSI-420和内标普萘洛, 用 C18 反相柱进行分离, 流动相为乙腈-5 mM甲酸铵 (35:65, v/v, pH = 3.0)。所有化合物均采用电喷雾电离源, 正离子方式检测。埃罗替尼和OSI-420的最低定量下限均为0.5 ng/mL。埃罗替尼的准确度在0.07%-8.00%范围内, OSI-420准确度在-2.83%-6.67%范围内; 埃罗替尼精密度在2.28%-15.12%范围内, OSI-420精密度在1.96%-11.50%范围内。此方法应用于BALB/c裸鼠口服12.5 mg/kg埃罗替尼的药代动力学研究中, 并用二室模型拟合埃罗替尼的药代动力学, 一室模型拟合OSI-420的药代动力学。代谢为OSI-420的埃罗替尼占埃罗替尼总量的10%, 比文献中的这一比值大一倍, 表明种属间埃罗替尼的代谢存在差异。

关键词: 埃罗替尼, OSI-420, 液质联用, 药代动力学, BALB/c裸鼠

Abstract:

A simple, rapid and sensitive LC-MS/MS method was developed to quantify erlotinib and its active metabolite, OSI-420, simultaneously in BALB/c nude mice plasma. Erlotinib, OSI-420 and propranolol (internal standard) were extracted from nude mice plasma samples by liquid-liquid extraction. Separation was achieved on a reversed phase C18 column with a mobile phase of acetonitrile-water (35:65, v/v) containing 5 mM ammonium formate (pH = 3.0). All compounds were monitored by mass spectrometry with electrospray positive ionization. The lower limit of quantification was 0.5 ng/mL for both erlotinib and OSI-420; accuracy was estimated by relative error, which was in the range from 0.07% to 8.00% for erlotinib and -2.83% to 6.67% for OSI-420; precision was validated by relative standard deviation, which was from 2.28% to 15.12% for erlotinib and from 1.96% to 11.50% for OSI-420. This method was applied to a pharmacokinetic study of BALB/c nude mice following oral administration of erlotinib at 12.5 mg/kg. A 2-compartment model was used to fit the pharmacokinetics of erlotinib and 1-compartment model for the pharmacokinetics of OSI-420. The ratio of the active metabolite to parent drug in mice was greater than previously reported in humans and probably reflects interspecies difference in the rate of conversion of erlotinib to OSI-420.

Key words: Erlotinib, OSI-420, LC-MS/MS, Pharmacokinetics, BALB/c nude mice

中图分类号:

R969.1

Supporting:

Foundation items: National Integrity Innovational Technology Platform of New Drug and Development (Grant No. 2009ZX09301-010), Innovation Team of Ministry of Education (Grant No. BMU20110263).
^*Corresponding author. Tel./Fax: 86-10-82801717

李梦瑶1,2, 吴琼2, 李汉青2, 宁妙然2, 陈烨2, 李良1,2, 周田彦1,2*, 卢炜1,2*. 液质联用法同时测定埃罗替尼及其活性代谢产物OSI-420在BALB/c裸鼠体内的浓度及其药代动力学研究[J]. , DOI: 10.5246/jcps.2012.04.040.

Meng-Yao Li, Qiong Wu, Han-Qing Li, Miao-Ran Ning, Ye Chen, Liang Li, Tian-Yan Zhou^*, Wei Lu^* . A sensitive LC-MS/MS method to determine the concentrations of erlotinib and its active metabolite OSI-420 in BALB/c nude mice plasma simultaneously and its application to a pharmacokinetic study [J]. , DOI: 10.5246/jcps.2012.04.040.

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