高效液相色谱法测定肿瘤模型BALB/c裸鼠血浆中埃罗替尼的浓度及其药代动力学研究

doi:10.5246/jcps.2011.03.030

高效液相色谱法测定肿瘤模型BALB/c裸鼠血浆中埃罗替尼的浓度及其药代动力学研究

李汉青, 陈烨, 李载权, 邓晨辉, 李良, 毕姗姗, 李梦瑶, 周田彦^*, 卢炜^*

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
3. 北京大学医学部基础医学院病理学系, 北京 100191

收稿日期:2011-03-07 修回日期:2011-04-22 出版日期:2011-05-06 发布日期:2011-05-06
通讯作者: 周田彦*, 卢炜*

A high performance liquid chromatography method for the quantitative
determination of erlotinib in the plasma of tumor bearing BALB/c nude
mice and its application in a pharmacokinetic study

Han-Qing Li, Ye Chen, Zai-Quan Li, Chen-Hui Deng, Liang Li, Shan-Shan Bi, Meng-Yao 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
3. Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China

Received:2011-03-07 Revised:2011-04-22 Online:2011-05-06 Published:2011-05-06
Contact: Tian-Yan Zhou*, Wei Lu*

摘要/Abstract

摘要：

本试验建立并验证了测定肿瘤模型BALB/c裸鼠血浆中表皮生长因子受体抑制剂埃罗替尼血药浓度的高效液相色谱方法。使用液液萃取的方法, 用甲基叔丁醚与乙酸乙酯 (9:1, v/v) 的混合溶剂将血浆中埃罗替尼和内标3-(6,7-双(2-甲氧基乙基)喹唑啉-4-氨基)苯乙酮提取。使用Luna C18 (4.6 mm×250 mm, 5 μm) 分析柱, 流动相为乙腈-5 mM的KH2PO4 缓冲盐 (41:59, v/v), pH为5.2, 紫外检测波长为345 nm, 流速为1.0 mL/min。本方法在20-10 000 ng/mL的浓度范围内具有良好的线性关系, 并且具有可接受的日内和日间精密度和准确度, 精密度在1.69%-5.66%的范围内, 准确度在105%-113%的范围内。埃罗替尼和内标的平均提取回收率分别为85.3% 和96.1%。该方法成功地运用到肿瘤模型BALB/c裸鼠单剂量口服给药12.5 mg/kg埃罗替尼后的药代动力学研究, 主要的药动学参数如下: Cmax为4.67 μg/mL, Tmax 为1.0 h, T1/2 为2.78 h, AUC0-24 h为18.0 μg/mL∙h。

关键词: 埃罗替尼, 高效液相色谱法, 液液萃取, 药代动力学, 表皮生长因子受体, 肿瘤

Abstract:

A new HPLC-UV method was developed and validated for the quantitative determination of epidermal growth factor receptor inhibitor erlotinib in the plasma of tumor bearing BALB/c nude mice. Erlotinib and its internal standard 1-(3-((6,7-bis (2-methoxyethoxy) quinazolin-4-yl) amino) phenyl) ethanone were extracted from mice plasma samples using liquid-liquid extraction with a mixed solvent of methyl t-butyl ether and ethyl acetate (9:1, v/v). Chromatographic separation was performed on a Luna C18 column (4.6 mm×250 mm, 5 μm) with acetonitrile: 5 mM potassium phosphate buffer pH = 5.2 (41:59, v/v) as the mobile phase. UV detector was set at the wavelength of 345 nm, and the flow rate was 1.0 mL/min. The calibration curve was linear over the range of 20-10 000 ng/mL with acceptable intra- and inter-day precision and accuracy. The intra-day and inter-day precisions were within the range of 1.69%-5.66%, and the accuracies of intra- and inter-day assays were within the range of 105%-113%. The mean recoveries were 85.2% and 96.1% for erlotinib and IS, respectively. This method was successfully applied to a pharmacokinetic study in tumor bearing BALB/c nude mice following single oral administration at the dose of 12.5 mg/kg. The main pharmacokinetic parameters were as follows: Cmax was 4.67 μg/mL, Tmax was 1.0 h, T1/2 was 2.78 h, and AUC0-24 h was 18.0 μg/mL∙h.

Key words: Erlotinib, HPLC-UV, Liquid-liquid extraction, Pharmacokinetics, Epidermal growth factor receptor, Tumor

中图分类号:

R969.1

Supporting:

Foundation item: National Integrity Innovational Technology Platform of New Drug and Development (Grant No. 2009ZX09301-010).
^*Corresponding author. Tel./fax: 86-10-82801717

李汉青, 陈烨, 李载权, 邓晨辉, 李良, 毕姗姗, 李梦瑶, 周田彦^*, 卢炜^*. 高效液相色谱法测定肿瘤模型BALB/c裸鼠血浆中埃罗替尼的浓度及其药代动力学研究[J]. , DOI: 10.5246/jcps.2011.03.030.

Han-Qing Li, Ye Chen, Zai-Quan Li, Chen-Hui Deng, Liang Li, Shan-Shan Bi, Meng-Yao Li, Tian-Yan Zhou^*, Wei Lu^* . A high performance liquid chromatography method for the quantitative
determination of erlotinib in the plasma of tumor bearing BALB/c nude
mice and its application in a pharmacokinetic study[J]. , DOI: 10.5246/jcps.2011.03.030.

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