Analytical strategies for the screening and evaluation of chemically reactive drug metabolites

Metabolic activation leading to formation of chemically reactive drug metabolites is a long-standing issue for drug development inasmuch as some, but not all, reactive intermediates play a role as mediators of drug-induced toxicities. The risk assessment profile/decision-making guide requires a comprehensive understanding of bioactivation mechanism(s), quantitative magnitude and cellular consequences of this principal and continued safety attrition.

To evaluate analytical methodologies with improved sensitivity, selectivity and throughput for the analysis of reactive metabolites.

Identification and quantification of short-lived electrophilic intermediates through appropriate trapping experiments have become relatively straightforward. Minimizing the bioactivation potential of drug candidates during the discovery/lead optimization phase has been adopted as a default strategy. Together with advances of proteomics, metabolomics and toxicogenomics, an integrated multitier approach possibly provides a deeper insight into mechanistic aspects of drug-induced toxicities, and contributes to bridging the relationships between metabolic activation, drug-protein adduct formation and their toxicological consequences.