Imatinilb metabolite profiling in parallel to imatinib quantification in plasma of treated patients using liquid chromatography-mass spectrometry
Imatinilb metabolite profiling in parallel to imatinib quantification in plasma of treated patients using liquid chromatography-mass spectrometry
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DOI：
10.1002/jms.1369
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发表时间：
2008-06-01
影响因子：
2.3
通讯作者：
Biollaz, Jerome
中科院分区：
文献类型：
--
作者：
Rochat, Bertrand;Fayet, Aurelie;Biollaz, Jerome
除了影响母体药物的全身生物利用度外，药物代谢酶（DME）还可能产生临床感兴趣的生物活性和/或毒性代谢产物。我们研究了液相色谱-串联质谱（LC-MS/MS）同时分析患者血浆中母体药物和新鉴定代谢物的能力。抗癌药物伊马替尼（imatinib）被选为模型药物，因为它开辟了癌症治疗的新领域，并且是口服和长期给药的。此外，这种疗法也有耐药性和罕见但有时严重的副作用的报道。伊马替尼的定量及其血浆代谢产物的分析建立如下三个步骤：（1）一般样品提取和LC-MS/MS条件的设置，（2）使用人肝微粒体（HLM）或患者血浆样品进行体外孵育，通过LC-MS/MS鉴别代谢物，（3）同时测定38例患者血浆中伊马替尼和14种代谢物的浓度，并进行了部分或交叉方法验证，结果表明，在缺乏纯标准品的情况下，可以精确测定代谢物的浓度。初步结果表明，伊马替尼及其代谢产物的处置是相关的个体间变量和异常代谢产物的配置文件可以revealed.This文章强调，除了通常的治疗药物监测（TDM），LC-MS/MS方法可以同时记录一个完整的药物代谢概况，使各种相关性研究的临床利益。版权所有（c）2008约翰威利父子有限公司。
Besides affecting the systemic bioavailability of the parent drug, drug metabolizing enzymes (DMEs) may produce bioactive and/or toxic metabolites of clinical interest. We have investigated the capability to analyze simultaneously the parent drug and newly identified metabolites in patients' plasma by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS).The anticancer drug, imatinib, was chosen as a model drug because it has opened a new area in cancer therapy and is given orally and chronically. In addition, resistance and rare but sometimes severe side effects have been reported with this therapy.The quantification of imatinib and the profiling of its metabolites in plasma were established following three steps: (1) set-up of a generic sample extraction and LC-MS/MS conditions, (2) metabolite identification by LC-MS/MS using either in vitro incubations performed with human liver microsomes (HLMs) or patient plasma samples, (3) the simultaneous determination of plasma levels of imatinib and 14 metabolites in the plasma samples of 38 patients.Partial or cross method validation has been done and revealed that precise determinations of metabolite levels can be performed whereas pure standards are not available. Preliminary results indicate that the disposition of imatinib and its metabolites is related to interindividual variables and that outlier metabolite profiles can be revealed.This article underscores that, in addition to usual therapeutic drug monitoring (TDM), LC-MS/MS methods can simultaneously record a complete drug metabolic profile enabling various correlation studies of clinical interest. Copyright (c) 2008 John Wiley & Sons, Ltd.