Simultaneous online SPE-HPLC-MS/MS analysis of docetaxel, temsirolimus and sirolimus in whole blood and human plasma
Simultaneous online SPE-HPLC-MS/MS analysis of docetaxel, temsirolimus and sirolimus in whole blood and human plasma
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DOI：
10.1016/j.jchromb.2013.01.017
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发表时间：
2013-03-15
影响因子：
3
通讯作者：
Garcia, Antonia
中科院分区：
文献类型：
--
作者：
Navarrete, Alicia;Paz Martinez-Alcazar, M.;Garcia, Antonia
多西他赛和替西罗莫司是广泛的实体瘤中最常用的药物。在临床前研究中，mTOR抑制剂如替西罗莫司已显示出与紫杉烷类的协同细胞毒性作用，为联合研究提供了理论基础。这些抗癌药物的治疗浓度范围较窄，并且由于其个体间和个体内的药代动力学变异性较高，因此通过高灵敏度方法（如LC-MS/MS）进行治疗剂量监测对于临床研究非常重要。因此，本研究的目的是开发和验证一种灵敏，快速，方便的方法，同时鉴定和定量多西他赛，替西罗莫司及其主要代谢物，西罗莫司，使用紫杉醇，另一种抗癌药物，作为内标。采用在线固相萃取-高效液相色谱-串联质谱（SPE-HPLC-MS/MS）联用技术对样品进行定量分析。在Zorbax eclipse XDB-C8（150 mm × 4.6 mm，5 μ m）柱上进行分离。质谱仪串联四极检测器配备有喷射流电喷雾离子化，在多反应监测（MRM）中监测，并在正模式下操作。使用甲醇/硫酸锌（70：30）（v/v）进行蛋白质沉淀，并使用Zorbax eclipse plus C8（12.5 mm x 4.6 mm，5 μ m）柱进行在线SPE，以提取化合物。该方法允许使用相同的试剂、样品处理和分析技术，而与样品是全血还是血浆无关。该方法已成功地验证和应用于真实的样品。这是一种用于剂量调整和评价联合治疗期间潜在药物相互作用的合适方法。(C)2013爱思唯尔有限公司版权所有。
Docetaxel and temsirolimus are some of the most used drugs in a wide range of solid tumors. In preclinical studies, mTOR inhibitors such as temsirolimus have demonstrated synergistic cytotoxic effects with taxanes providing the rationale for combination studies. These anticancer agents exhibit a narrow therapeutic concentration range and due to their high inter- and intra-individual pharmacokinetic variability, therapeutic dose monitoring by highly sensitive methods as LC-MS/MS are important for clinical research. Therefore, the aim of this study was to develop and validate a sensitive, fast and convenient method for the simultaneous identification and quantification of docetaxel, temsirolimus and its main metabolite, sirolimus, using paclitaxel, another anticancer drug, as the internal standard. These analytes were quantified by an integrated online solid phase extraction-high performance liquid chromatography-tandem mass spectrometry (SPE-HPLC-MS/MS) system. Separation was performed on a Zorbax eclipse XDB-C8 (150 mm x 4.6 mm, 5 mu m) column. The mass spectrometer tandem quadruple detector was equipped with jet stream electrospray ionization, monitored in multiple reactions monitoring (MRM) and operated in positive mode. A combination of protein precipitation with methanol/zinc sulphate (70:30) (v/v) and online SPE using a Zorbax eclipse plus C8 (12.5 mm x 4.6 mm, 5 mu m) cartridge was used to extract the compounds. This method allows the use of the same reagents, sample treatment and analytical technique independently of whether the samples are whole blood or plasma. The method has been successfully validated and applied to real samples. It is a suitable method for dose adjustment and for evaluating potential drug interactions during combined treatments. (C) 2013 Elsevier B.V. All rights reserved.