Application of Electro-Activated Dissociation Fragmentation Technique to Identifying Glucuronidation and Oxidative Metabolism Sites of Vepdegestrant by Liquid Chromatography-High Resolution Mass Spectrometry
文献类型：期刊论文
| 作者 | He, Yifei5,6; Hou, Pengyi4; Long, Zhimin4; Zheng, Yuandong5,6; Tang, Chongzhuang3; Jones, Elliott2; Diao, Xingxing5,6; Zhu, Mingshe1,3 |
| 刊名 | DRUG METABOLISM AND DISPOSITION
 |
| 出版日期 | 2024-07-01 |
| 卷号 | 52期号:7页码:634-643 |
| ISSN号 | 0090-9556 |
| DOI | 10.1124/dmd.124.001661 |
| 通讯作者 | Diao, Xingxing(xxdiao@simm.ac.cn) ; Zhu, Mingshe(mingshe.zhu@yahoo.com) |
| 英文摘要 | Drug metabolite identification is an integrated part of drug metabolism and pharmacokinetics studies in drug discovery and development. Definitive identification of metabolic modification sides of test compounds such as screening metabolic soft spots and supporting metabolite synthesis are often required. Currently, liquid chromatography-high resolution mass spectrometry is the dominant analytical platform for metabolite identification. However, the interpretation of product ion spectra generated by commonly used collision-induced disassociation (CID) and higher-energy collisional dissociation (HCD) often fails to identify locations of metabolic modifications, especially glucuronidation. Recently, a ZenoTOF 7600 mass spectrometer equipped with electron-activated dissociation (EAD-HRMS) was introduced. The primary objective of this study was to apply EAD-HRMS to identify metabolism sites of vepdegestrant (ARV-471), a model compound that consists of multiple functional groups. ARV-471 was incubated in dog liver microsomes and 12 phase I metabolites and glucuronides were detected. EAD generated unique product ions via orthogonal fragmentation, which allowed for accurately determining the metabolism sites of ARV-471, including phenol glucuronidation, piperazine N-dealkylation, glutarimide hydrolysis, piperidine oxidation, and piperidine lactam formation. In contrast, CID and HCD spectral interpretation failed to identify modification sites of three O-glucuronides and three phase I metabolites. The results demonstrated that EAD has significant advantages over CID and HCD in definitive structural elucidation of glucuronides and phase I metabolites although the utility of EAD-HRMS in identifying various types of drug metabolites remains to be further evaluated. SIGNIFICANCE STATEMENT Definitive identification of metabolic modification sites by liquid chromatography-high resolution mass spectrometry is highly needed in drug metabolism research, such as screening metabolic soft spots and supporting metabolite synthesis. However, commonly used collision-induced dissociation (CID) and higher- energy collisional dissociation (HCD) fragmentation techniques often fail to provide critical information for definitive structural elucidation. In this study, the electron-activated dissociation (EAD) was applied to identifying glucuronidation and oxidative metabolism sites of vepdegestrant, which generated significantly better results than CID and HCD. |
| WOS关键词 | THOROUGH BACKGROUND SUBTRACTION ; LC/MS DATA APPLICATION ; DATA-ACQUISITION ; BIOLOGICAL MATRICES ; HIGH-THROUGHPUT ; IDENTIFICATION ; DEFECT ; ALGORITHM ; METABOLOMICS ; SYSTEM |
| 资助项目 | National Natural Science Foundation of China[82373938] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001335739700006 |
| 出版者 | AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/313990]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Diao, Xingxing; Zhu, Mingshe |
| 作者单位 | 1.Mass Defect Technol, Princeton, NJ 08540 USA 2.AB Sciex LLC, Framingham, MA USA 3.XenoFinder Co Ltd, Suzhou, Peoples R China 4.SCIEX Ltd, Beijing, Peoples R China 5.Univ Chinese Acad Sci, Beijing, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai, Peoples R China |
| 推荐引用方式 GB/T 7714 | He, Yifei,Hou, Pengyi,Long, Zhimin,et al. Application of Electro-Activated Dissociation Fragmentation Technique to Identifying Glucuronidation and Oxidative Metabolism Sites of Vepdegestrant by Liquid Chromatography-High Resolution Mass Spectrometry[J]. DRUG METABOLISM AND DISPOSITION,2024,52(7):634-643. |
| APA | He, Yifei.,Hou, Pengyi.,Long, Zhimin.,Zheng, Yuandong.,Tang, Chongzhuang.,...&Zhu, Mingshe.(2024).Application of Electro-Activated Dissociation Fragmentation Technique to Identifying Glucuronidation and Oxidative Metabolism Sites of Vepdegestrant by Liquid Chromatography-High Resolution Mass Spectrometry.DRUG METABOLISM AND DISPOSITION,52(7),634-643. |
| MLA | He, Yifei,et al."Application of Electro-Activated Dissociation Fragmentation Technique to Identifying Glucuronidation and Oxidative Metabolism Sites of Vepdegestrant by Liquid Chromatography-High Resolution Mass Spectrometry".DRUG METABOLISM AND DISPOSITION 52.7(2024):634-643. |
入库方式： OAI收割
来源：上海药物研究所
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