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Metabolite identification in drug discovery
Alan P Watt1, Russell J Mortishire-Smith, Ute Gerhard
1Merck Sharp and Dohme Research Laboratories, Department of Medicinal Chemistry (Drug Metabolism Section), Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex, CM20 2QR, UK. alan_watt@merck.com
Current Opinion in Drug Discovery & Development
|March 5, 2003
Summary
This review covers advanced methods for identifying drug metabolites in drug discovery. Key techniques include mass spectrometry and nuclear magnetic resonance spectroscopy for precise structural analysis.
Area of Science:
- Pharmacology and Drug Discovery
- Analytical Chemistry
- Biochemistry
Background:
- Metabolite identification is crucial for drug discovery and development.
- Traditional methods for metabolite analysis face limitations in sensitivity and scope.
Purpose of the Study:
- To review recent technological advancements in metabolite identification for drug discovery.
- To highlight novel approaches for sample generation and metabolite isolation.
- To discuss improvements in detection and structural elucidation techniques.
Main Methods:
- In vitro systems (microsomes, hepatocytes) and in vivo studies (excreta) for metabolite generation.
- Recombinant enzymes and microorganisms as alternative metabolite sources.
- Solid-phase microextraction and preparative chromatography for metabolite isolation.
- Mass spectrometry (high-resolution TOF, Q-TOF) for detection and structural elucidation.
- Nuclear magnetic resonance (NMR) spectroscopy with advanced magnets and hyphenation techniques for definitive structural analysis.
Main Results:
- Significant improvements in mass spectrometry sensitivity and selectivity enable detection of low-abundance metabolites.
- Advancements in chromatography, particularly mass-directed detection, enhance metabolite isolation.
- NMR spectroscopy, driven by higher field strengths and hyphenation, provides definitive structural elucidation.
- New techniques like solid-phase microextraction aid in isolating metabolites from complex biological matrices.
Conclusions:
- Recent technological developments have substantially enhanced metabolite identification capabilities in drug discovery.
- Mass spectrometry and NMR spectroscopy are pivotal tools for sensitive detection and precise structural elucidation.
- These advancements facilitate a more comprehensive understanding of drug metabolism, aiding in the development of safer and more effective therapeutics.