Metabolomics-Based Approaches To Determine Drug Metabolite Profiles

Analytical technology forms the backbone of all absorption, distribution, metabolism and excretion (ADME)-related research and by far the most important single analytical technology is mass spectrometry (MS). The introduction of routine use high resolution high-resolution (HR) mass spectrometers over the last decade has provided an opportunity to greatly improve and enhance ADME scientists' abilities to conduct both qualitative and quantitative profiling of drug metabolites. Two of the most challenging tasks in metabolite identification by LC/MS are: (1) the rapid assignment of full scan and MS/MS spectra obtained from in vitro samples during the candidate optimization phase; and (2) the comprehensive detection and structural elucidation of all drug-related metabolites, including those that could be considered trace, either arising from predictable or unpredictable biotransformations in the presence of large amounts of complex interference ions from endogenous components. HR-MS can play a unique role in both of these key activities as well as other workflows in the ADME-related realm. This chapter will consider the utility of HR-MS in multiple aspects of drug metabolite detection in candidate optimization and characterization.