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ADME PK

Reactive metabolite assessment

  • Reactive metabolite formation is thought to be one of the primary causes of idiosyncratic adverse drug reactions, often associated with drug-induced skin, liver and hematopoietic toxicities.
  • Reactive metabolites are electrophilic species which can bind covalently to macromolecules such as proteins and DNA, affecting their function and potentially leading to toxicity.
  • To minimize the risk of later stage failure - which is of considerable financial burden to the Pharmaceutical Industry - screening for reactive metabolite formation at an early stage in lead optimization is now becoming common practice1.
  • Chemical trapping agents, such as reduced glutathione (GSH), can form stable adducts with many reactive species. Trapping agents, incubated with liver microsomes, are now routinely used in the identification and characterization of reactive metabolites.
  • Cyprotex have invested in an Applied Biosystems QTRAP® 5500, one of the most sensitive ion trap and triple quadrupole instruments in the industry. This instrument improves detection of the conjugates and allows superior fragmentation pattern and spectrum confirmation.
  • Cyprotex offer glutathione trapping studies using human liver microsomes and LC-MS/MS detection.
Screening and structural characterization of reactive metabolites, as one of the major efforts to reduce attrition in drug development, has increasingly become an integral part of the ADMET-guided lead optimization process in drug discovery.

2 Yan Z, Maher N, Torres R, Caldwell GW and Huebert N (2005) Rapid Commun Mass Spectrom 19; 3322-3330

References

1 Evans DC et al. (2004) Chem Res Toxicol 17(1); 3-16
2 Yan Z et al. (2005) Rapid Commun Mass Spectrom 19; 3322-3330

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