Shuguang Ma, Swapan K. Chowdhury and Kevin B. Alton Pages 503 - 523 ( 21 )
Metabolism studies play a pivotal role in drug discovery and development. Characterization of metabolic "hot-spots" as well as reactive and pharmacologically active metabolites is critical to designing new drug candidates with im-proved metabolic stability, toxicological profile and efficacy. Metabolite identification in the preclinical species used forsafety evaluation is required in order to determine whether human metabolites have been adequately tested during non-clinical safety assessment. From an instrumental standpoint, high performance liquid chromatography (HPLC) coupledwith mass spectrometry (MS) dominates all analytical tools used for metabolite identification. The general strategies em-ployed for metabolite identification in both drug discovery and drug development settings together with sample prepara-tion techniques are reviewed herein. These include a discussion of the various ionization methods, mass analyzers, andtandem mass spectrometry (MS/MS) techniques that are used for structura l characterization in a modern drug metabolismlaboratory. Mass spectrometry-based techniques, such as stable isotope labeling, on-line H/D exchange, accurate massmeasurement to enhance metabolite identification and recent improvements in data acquisition and processing for acceler-ating metabolite identification are also described. Rounding out this review, we offer additional thoughts about the poten-tial of alternative and less frequently used techniques such as LC-NMR/MS, CRIMS and ICPMS.
Metabolite identification, LC-MS/MS, H/D exchange, mass spectrometry, accurate mass measurement, APPI, CRIMS, ICPMS, LC-NMR/MS
Department of Drug Metabo-lism and Pharmacokinetics, Schering-Plough Research Institute, 2015 Gal-loping Hill Road, Kenilworth, NJ 07033, USA.