Applications of mass spectrometry in drug metabolism: 50 years of progress

Abstract

Mass spectrometry plays a pivotal role in drug metabolism studies, which are an integral part of drug discovery and development nowadays. Metabolite identification has become critical to understanding the metabolic fate of drug candidates and to aid lead optimization with improved metabolic stability, toxicology and efficacy profiles. Ever since the introduction of atmospheric ionization techniques in the early 1990s, liquid chromatography coupled with mass spectrometry (LC/MS) has secured a central role as the predominant analytical platform for metabolite identification as LC and MS technologies continually advanced. In this review, we discuss the evolution of both MS technology and its applications over the past 50 years to meet the increasing demand of drug metabolism studies. These advances include ionization sources, mass analyzers, a wide range of MS acquisition strategies and data mining tools that have substantially accelerated the metabolite identification process and changed the overall drug metabolism landscape. Exemplary applications for characterization and identification of both small-molecule xenobiotics and biological macromolecules are described. In addition, this review discusses novel MS technologies and applications, including xenobiotic metabolomics that hold additional promise for advancing drug metabolism research, and offers thoughts on remaining challenges in studying the metabolism and disposition of drugs and other xenobiotics.

The application of high-resolution mass spectrometry-based data-mining tools in tandem to metabolite profiling of a triple drug combination in humans

“…On the basis of the structures of MET, PAN and CLAR, the following common MDF templates were used to targeted metabolite detection of each drug: (1) the phase I metabolites formed by hydroxylation (m/z 188.0665 for MET, m/z 400.0773 for PAN, and m/z 764.4791 for CLAR) and demethylation (m/z 370.0668 for PAN, and m/z 734.4685 for CLAR); (2) the glucuronide of monohydroxylated PAN (m/z 576.1094); (3) loss of cladinose sugar from CLAR (m/z 590.3899); and (4) combination of (1), (2) and/or (3). Specifically, the mass defect filter windows were set to ± 40 mDa around the mass defects of the templates over a mass range of ± 50 Da of the filter templates.…”

High-resolution mass spectrometry in toxicology: current status and future perspectives

“…Application of HRMS in drug metabolism was reviewed by Meyer and Maurer (Meyer and Maurer 2012a), its historical progress by Wen and Zhu (2015), and corresponding data acquisition and mining by Ma and Chowdhury (2013). Meyer and Maurer (2012b) discussed the importance of the analytical strategies, software solutions, and the mass resolution and accuracy in drug metabolism studies using HRMS and Ma and Chowdhury how challenging the characterizing of small amounts of metabolites in large excess of endogenous matrices is.…”

Unraveling the in vitro and in vivo metabolism of diacetoxyscirpenol in various animal species and human using ultrahigh-performance liquid chromatography-quadrupole/time-of-flight hybrid mass spectrometry

“…Due to technical limitations of high-performance liquid chromatography used with a UV detector, analysis of trace metabolites is difficult [24]. Additionally, information on species-specific differences in metabolism of DAS is scarce.…”

“…In the past decade, mass spectrometry (MS) played a key role in drug metabolite identification [24]. The development of high-resolution MS with improved accuracy and stability, along with new data processing techniques, improved the quality and productivity of metabolite identification processes [25].…”