An integrated approach for profiling oxidative metabolites and glutathione adducts using liquid chromatography coupled with ultraviolet detection and triple quadrupole-linear ion trap mass spectrometry
An integrated approach for profiling oxidative metabolites and glutathione adducts using liquid chromatography coupled with ultraviolet detection and triple quadrupole-linear ion trap mass spectrometry
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DOI：
10.1016/j.jpba.2016.07.048
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发表时间：
2016-09-10
影响因子：
3.4
通讯作者：
Zhu, Mingshe
中科院分区：
文献类型：
--
作者：
Chen, Guiying;Cheng, Zhongzhe;Zhu, Mingshe
使用液相色谱 (LC) 与三重四极杆线性离子阱 (Qtrap) 质谱 (MS) 结合进行药物代谢和药代动力学研究中的定量和定性分析引起了人们的极大兴趣。在此，报道了一种基于 Qtrap 的新分析方法，用于同时检测、结构表征和半定量体外氧化代谢物和谷胱甘肽捕获的反应性代谢物。在当前的研究中，结合多离子监测和多反应监测作为测量扫描，分别触发氧化代谢物和谷胱甘肽加合物的产物离子光谱采集。然后，使用多种数据挖掘方法完成代谢物的检测和 MS/MS 谱图的恢复。此外，还采用在线紫外线 (UV) 检测来确定主要代谢物的相对浓度。对大鼠肝微粒体中氯氮平和诺米芬辛代谢物的分析不仅揭示了多种氧化代谢物和谷胱甘肽加合物，而且还确定了它们的主要氧化代谢和生物活化途径。结果表明，LC/UV/MS 方法使 Qtrap 能够在体外对氧化代谢物和谷胱甘肽加合物进行全面分析。 (C) 2016 Elsevier B.V. 保留所有权利。
The use of liquid chromatography (LC) coupled with triple quadrupole linear ion trap (Qtrap) mass spectrometry (MS) for both quantitative and qualitative analysis in drug metabolism and pharmacokinetic studies is of great interest. Here, a new Qtrap-based analytical methodology for simultaneous detection, structural characterization and semi-quantitation of in vitro oxidative metabolites and glutathione trapped reactive metabolites was reported. In the current study, combined multiple ion monitoring and multiple reaction monitoring were served as surveying scans to trigger product ion spectral acquisition of oxidative metabolites and glutathione adduct, respectively. Then, detection of metabolites and recovery of their MS/MS spectra were accomplished using multiple data mining approaches. Additionally, online ultraviolet (UV) detection was employed to determine relative concentrations of major nietabolites. Analyses of metabolites of clozapine and nomifensine in rat liver microsomes not only revealed multiple oxidative metabolites and glutathione adducts, but also identified their major oxidative metabolism and bioactivation pathways. The results demonstrated that the LC/UV/MS method enabled Qtrap to perform the comprehensive profiling of oxidative metabolites and glutathione adducts in vitro. (C) 2016 Elsevier B.V. All rights reserved.