Metabolite identification in drug discovery.

Curr Opin Drug Discov Devel

Merck Sharp and Dohme Research Laboratories, Department of Medicinal Chemistry (Drug Metabolism Section), Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex, CM20 2QR, UK.

Published: January 2003

AI Article Synopsis

  • - Recent advancements in drug discovery focus on technologies for identifying metabolites, using both in vitro systems (like liver fractions and whole cells) and in vivo methods through excretion from test species after dosing.
  • - New methods, including solid-phase microextraction, are being applied for metabolite isolation, although preparative chromatography remains the primary technique, aided by improved mass-directed detection.
  • - Mass spectrometry has seen significant enhancements in sensitivity and selectivity for metabolite detection, while nuclear magnetic resonance spectroscopy continues to evolve with higher field magnets and innovative probe designs as a leading tool for elucidating molecular structures.

Article Abstract

Recent developments in the technologies and approaches to identify metabolites in a drug discovery environment are reviewed. Samples may be generated using either in vitro systems--typically, but not exclusively, liver subcellular fractions, such as microsomes, or whole cells, such as hepatocytes. Alternatively, metabolites are generated in vivo using excreta obtained following dosing in preclinical species. Recombinant drug metabolizing enzymes or microorganisms may offer alternate vectors. New techniques, such as the use of solid-phase microextraction, have found application in the isolation of metabolites from biological matrices. However, this is still dominated by the use of preparative chromatography, which has advanced through the use of mass-directed detection. Detection and structural elucidation by mass spectrometry have improved markedly with increases in sensitivity, allowing lower abundance metabolites to be detected, and increases in selectivity, with the use of high-resolution time-of-flight and quadrupole-time-of-flight instruments. Finally, higher field strength magnets coupled with novel probe designs and increased use of liquid chromatographic hyphenation techniques continue to drive the capabilities of nuclear magnetic resonance spectroscopy as the definitive structural elucidation tool.

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