Application of mass spectrometry for metabolite identification.
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 improved metabolic stability, toxicological profile and efficacy. Metabolite identification in the preclinical species used for safety 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) coupled with mass spectrometry (MS) dominates all analytical tools used for metabolite identification. The general strategies employed for metabolite identification in both drug discovery and drug development settings together with sample preparation techniques are reviewed herein. These include a discussion of the various ionization methods, mass analyzers, and tandem mass spectrometry (MS/MS) techniques that are used for structural characterization in a modern drug metabolism laboratory. Mass spectrometry-based techniques, such as stable isotope labeling, on-line H/D exchange, accurate mass measurement to enhance metabolite identification and recent improvements in data acquisition and processing for accelerating metabolite identification are also described. Rounding out this review, we offer additional thoughts about the potential of alternative and less frequently used techniques such as LC-NMR/MS, CRIMS and ICPMS.
Ma
Shuguang
S
Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. swapan.chowdhury@spcorp.com
Chowdhury
Swapan K
SK
Alton
Kevin B
KB
D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D041961:Deuterium Exchange Measurement; D005583:Fourier Analysis; D006801:Humans; D016247:Information Storage and Retrieval; D007553:Isotope Labeling; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D013058:Mass Spectrometry / Q000379:methods / Q000639:trends; D008832:Microchemistry / Q000379:methods; D015394:Molecular Structure; D008970:Molecular Weight; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D013048:Specimen Handling / Q000379:methods; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods; D013678:Technology, Pharmaceutical / Q000379:methods / Q000639:trends
D004364:Pharmaceutical Preparations