Safety Assessment of Drug Metabolites: Characterization of Chemically Stable Metabolites

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• 作者：W. Griffith Humphreys ; Steve E. Unger
• 刊名：Chemical Research in Toxicology
• 出版年：2006
• 出版时间：December 2006
• 年：2006
• 卷：19
• 期：12
• 页码：1564 - 1569
• 全文大小：40K
• 年卷期：v.19,no.12(December 2006)
• ISSN：1520-5010

文摘

Drug molecules are typically subjected to a variety of biotransformation reactions, and the metabolitesformed through these reactions must be considered when conducting safety testing programs for newchemical entities. Metabolites that are chemically stable sometimes have pharmacological activity profilessimilar to those of the parent compound but rarely have potent activity against off-target receptors thatis unique relative to the parent profile. This fact argues for the thorough testing of drug metabolites fortheir pharmacological activity. It also argues for a significantly lower need for the thorough characterizationand quantitation of stable metabolites not thought to substantially contribute to the pharmacodynamiceffect. Given the tremendous resource requirements involved in the thorough characterization of drugmetabolites, a more flexible, tiered approach to stable metabolite characterization would seem to providethe best utilization of resources while still allowing a complete evaluation of the toxicological profile ofa new drug.