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Metabolite Synthesis and Identification
In February 2008, the FDA released a guidance providing recommendations to drug companies on how and when they should evaluate the toxicity of human drug metabolites. Metabolites, formed from Phase 1 reactions, detected in the body in quantities greater than 10% are recommended for toxicity studies before beginning large-scale clinical trials. For 
supplemental reading: FDA Industry Guidance  and  ACS Publication

CURRENT ISSUES - associated with using biological systems to screen for metabolites

1) Studies completed in vitro produce very small quantities of the desired metabolite in addition to being hydrophilic and difficult to isolate. 
2) Phase 1 metabolite studies in animals are expensive and require the sacrifice of the animal. Another challenge is quantifying the precise stoichiometry of the oxidant because variable amounts are present in liver slice preparations. 
3) Pharmacologists have no prior knowledge about the structure of the metabolites they should be seeking. 
4) Many of the metabolites are not amenable to organic synthesis using conventional routes. 

OUR SOLUTIONS​  - metalloporphyrins as mimics of the in vivo metabolic process

Metabolite Synthesis 
​1) Proprietary metalloporphyrins (P450 mimics)
2) Electrochemical methods (Antec Roxy EC-MS reactor)
3) Custom organic synthesis from synthetic building blocks 

Metabolite Identification, Isolation, and/or Analysis
1) 500 MHz NMR and 600 MHz cryoprobe NMR
2) Solid phase extraction (SPE)
3) LCMS-SPE-NMR combo
Example Phase I Reactions
  • Oxidation
  • Reduction
  • Hydrolytic cleavage
  • Alkylation (Methylation)
  • Dealkylation
  • Ring cyclization
  • N-carboxylation
  • Dimerization
  • Transamidation
  • Isomerization
  • Decarboxylation
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