Bo Wen1, William L Fitch. 1. Department of Drug Metabolism and Pharmacokinetics, Roche Palo Alto, Palo Alto, CA 94304, USA. bo.wen@roche.com
Abstract
BACKGROUND: 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. OBJECTIVE: To evaluate analytical methodologies with improved sensitivity, selectivity and throughput for the analysis of reactive metabolites. CONCLUSIONS: 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.
BACKGROUND: 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. OBJECTIVE: To evaluate analytical methodologies with improved sensitivity, selectivity and throughput for the analysis of reactive metabolites. CONCLUSIONS: 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.
Authors: D Calligaris; P Verdier-Pinard; F Devred; C Villard; D Braguer; Daniel Lafitte Journal: Cell Mol Life Sci Date: 2010-01-28 Impact factor: 9.261