Future of Toxicology-Metabolic Activation and Drug Design: Challenges and Opportunities in Chemical Toxicology

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• 作者：Thomas A. Baillie
• 刊名：Chemical Research in Toxicology
• 出版年：2006
• 出版时间：July 2006
• 年：2006
• 卷：19
• 期：7
• 页码：889 - 893
• 全文大小：41K
• 年卷期：v.19,no.7(July 2006)
• ISSN：1520-5010

文摘

The issue of chemically reactive drug metabolites is one of growing concern in the pharmaceuticalindustry inasmuch as some, but not all, reactive intermediates are believed to play a role as mediators ofdrug-induced toxicities. While it is now relatively straightforward to identify these short-lived electrophilicspecies through appropriate in vitro "trapping" experiments, our current understanding of mechanisticaspects of xenobiotic-induced toxicities is such that we cannot predict which reactive intermediates arelikely to cause a toxic insult and which will be benign. Little is known about the identities of themacromolecular targets (primarily proteins) of these electrophiles or the functional consequences of theircovalent modification by reactive drug metabolites. As a result, several companies have adopted approachesto minimize the potential for metabolic activation of drug candidates at the discovery/lead optimizationphase as a default strategy. However, research leading to a deeper insight into mechanistic aspects oftoxicities caused by reactive drug metabolites will aid greatly in the rational design of drug candidateswith superior safety profiles and represents a challenging and exciting opportunity for chemical toxicology.