Biological reactive intermediates in drug discovery and development: a perspective from the pharmaceutical industry.

Abstract

The detection of chemically-reactive, electrophilic metabolites poses a particular problem in the discovery and development of drug candidates in pharmaceutical research, inasmuch as it is not possible to accurately predict the likely toxicological consequences of these intermediates in animal safety studies or in clinical trials. Advances in analytical instrumentation (notably liquid chromatography-tandem mass spectrometry [LC-MS/MS]) have facilitated the detection of reactive intermediates through the identification of the glutathione (GSH) adducts to which they normally give rise, while the increased use of radiolabeled tracers in drug development permits an early assessment to be made of the propensity of a drug candidate to undergo covalent binding to cellular macromolecules. Unfortunately, these advances in analytical methods for the detection and characterization of reactive drug metabolites have far outstripped our understanding of the mechanisms of foreign compound-mediated toxicities at the molecular level, and of the role of both covalent binding and oxidative stress in the cascade of events that lead ultimately to cellular injury or immune-mediated toxicities. In light of these uncertainties, it seems reasonable to argue that one should attempt to minimize, through structural modification, the extent to which a drug candidate undergoes metabolism to reactive intermediates. Therefore, it becomes imperative to have close collaboration between Drug Metabolism scientists and their counterparts in Medicinal Chemistry during both the discovery and early development phases.