Detection of reactive metabolites using isotope-labeled glutathione trapping and simultaneous neutral loss and precursor ion scanning with ultra-high-pressure liquid chromatography triple quadruple mass spectrometry

Analytical Chemistry
Ke HuangR B van Breemen

Abstract

Metabolic activation of drugs to electrophilic species is responsible for over 60% of black box warnings and drug withdrawals from the market place in the United States. Reactive metabolite trapping using glutathione (GSH) and analysis using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) or HPLC with high resolution mass spectrometry (mass defect filtering) have enabled screening for metabolic activation to become routine during drug development. However, current MS-based approaches cannot detect all GSH conjugates present in complex mixtures, especially those present in extracts of botanical dietary supplements. To overcome these limitations, a fast triple quadrupole mass spectrometer-based approach was developed that can detect positively and negatively charged GSH conjugates in a single analysis without the need for advanced knowledge of the elemental compositions of potential conjugates and while avoiding false positives. This approach utilized UHPLC instead of HPLC to shorten separation time and enhance sensitivity, incorporated stable-isotope labeled GSH to avoid false positives, and used fast polarity switching electrospray MS/MS to detect GSH conjugates that form positive and/or negative io...Continue Reading

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Citations

Jan 7, 2016·Chemical Research in Toxicology·Richard A ThompsonDominic P Williams
Dec 23, 2015·Journal of Applied Toxicology : JAT·M José Gómez-LechónM Teresa Donato
Jul 1, 2015·Journal of Medicinal Chemistry·Richard B van Breemen
Aug 18, 2017·Angewandte Chemie·Jens AtzrodtMarc Reid
Aug 27, 2019·Drug Metabolism Reviews·Bo Wen, Peter Gorycki
Jul 25, 2019·ACS Applied Materials & Interfaces·Shengmei ZhuGuangfeng Wang
Nov 5, 2019·Chemical Research in Toxicology·Serat-E AliXiaoli Meng

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