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.

• Mass spectrometry
• drug metabolism
• biotransformation
• metabolite identification
• LC/MS
• high-resolution MS

Declaration of interest

The authors declare that there are no conflicts of interest.

Notes

* This article is dedicated to the memory of Professor Sidney D. Nelson. Bo Wen was a graduate student (2000–2005) and Mingshe Zhu was a postdoctoral fellow (1994–1996) under the mentorship of Dr. Nelson in University of Washington.