Simultaneous determination of apatinib and its four major metabolites in human plasma using liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic study
Simultaneous determination of apatinib and its four major metabolites in human plasma using liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic study
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DOI：
10.1016/j.jchromb.2012.03.027
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发表时间：
2012-05-01
影响因子：
3
通讯作者：
Zhong, Dafang
中科院分区：
文献类型：
--
作者：
Ding, Juefang;Chen, Xiaoyan;Zhong, Dafang
Apatinib，也被称为YN968D1，是一种新型抗血管生成药物，选择性抑制血管内皮生长因子受体-2。目前，阿帕替尼正在中国进行治疗实体瘤的II/III期临床试验。阿帕替尼在人体被广泛代谢，其在循环中的主要代谢物包括顺式-3-羟基-阿帕替尼（M1-1）、反式-3-羟基-阿帕替尼（M1-2）、阿帕替尼-25- n -氧化物（M1-6）和顺式-3-羟基-阿帕替尼-o -葡萄糖醛酸盐（M1-2）。为研究阿帕替尼及其四种主要代谢物在晚期结直肠癌患者体内的药代动力学，建立了一种灵敏、选择性的液相色谱-串联质谱法，并验证了同时测定人血浆中阿帕替尼、M1-1、M1-2、M1-6和M9-2的方法。以乙腈为沉淀溶剂进行简单蛋白质沉淀后，采用Zorbax Eclipse XDB C-18色谱柱（50 mm × 4.6 mm, 1.8 μ m, Agilent），乙腈：5 mmol/L乙酸铵，0.1%甲酸为流动相，梯度洗脱，分离所有分析物和内标vatalanib。色谱总运行时间为9 min。采用电喷雾电离法在正离子多反应监测模式下进行质谱检测。该方法在浓度范围为3.00 ~ 2000 ng/mL范围内呈线性关系。每种分析物的定量下限为3.00 ng/mL。所有分析物的分析内精密度小于11.3%，分析间精密度小于13.8%，准确度在-5.8% ~ 3.3%之间。该方法已成功应用于晚期结直肠癌患者口服甲磺酸阿帕替尼500 mg后的临床药代动力学研究。(C) 2012 Elsevier B.V.版权所有
Apatinib, also known as YN968D1, is a novel antiangiogenic agent that selectively inhibits vascular endothelial growth factor receptor-2. Currently, apatinib is undergoing phase II/III clinical trials in China for the treatment of solid tumors. Apatinib is extensively metabolized in humans, and its major metabolites in circulation include cis-3-hydroxy-apatinib (M1-1), trans-3-hydroxy-apatinib (M1-2), apatinib-25-N-oxide (M1-6), and cis-3-hydroxy-apatinib-O-glucuronide (M9-2). To investigate the pharmacokinetics of apatinib and its four major metabolites in patients with advanced colorectal cancer, a sensitive and selective liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous determination of apatinib, M1-1, M1-2, M1-6, and M9-2 in human plasma. After a simple protein precipitation using acetonitrile as the precipitation solvent, all the analytes and the internal standard vatalanib were separated on a Zorbax Eclipse XDB C-18 column (50 mm x 4.6 mm, 1.8 mu m, Agilent) using acetonitrile: 5 mmol/L ammonium acetate with 0.1% formic acid as the mobile phase with gradient elution. A chromatographic total run time of 9 min was achieved. Mass spectrometry detection was conducted through electrospray ionization in positive ion multiple reaction monitoring modes. The method was linear over the concentration range of 3.00-2000 ng/mL for each analyte. The lower limit of quantification for each analyte was 3.00 ng/mL. The intra-assay precision for all the analytes was less than 11.3%, the inter-assay precision was less than 13.8%, and the accuracy was between -5.8% and 3.3%. The validated method was successfully applied to a clinical pharmacokinetic study following oral administration of 500 mg apatinib mesylate in patients with advanced colorectal cancer. (C) 2012 Elsevier B.V. All rights reserved.