Drug-Protein Adducts: An Industry Perspective on Minimizing the Potential for Drug Bioactivation in Drug Discovery and Development

详细信息    查看全文

• 作者：David C. Evans ; Alan P. Watt ; Deborah A. Nicoll-Griffith ; and Thomas A. Baillie
• 刊名：Chemical Research in Toxicology
• 出版年：2004
• 出版时间：January 2004
• 年：2004
• 卷：17
• 期：1
• 页码：3 - 16
• 全文大小：181K
• 年卷期：v.17,no.1(January 2004)
• ISSN：1520-5010

文摘

It is generally accepted that there is neither a well-defined nor a consistent link betweenthe formation of drug-protein adducts and organ toxicity. Because the potential does exist,however, for these processes to be causally related, the general strategy at Merck ResearchLaboratories has been to minimize reactive metabolite formation to the extent possible byappropriate structural modification during the lead optimization stage. This requires a flexibleapproach to defining bioactivation issues in a variety of metabolism vectors and typicallyinvolves the initial use of small molecule trapping agents to define the potential forbioactivation. At some point, however, there is a requirement to synthesize a radiolabeled tracerand to undertake covalent binding studies in vitro, usually in liver microsomal (and sometimeshepatocyte) preparations from preclinical species and human, and also in vivo, typically inthe rat. This paper serves to provide one pragmatic approach to addressing the issue ofbioactivation from an industry viewpoint based on protocols adopted by Merck ResearchLaboratories. The availability of a dedicated Labeled Compound Synthesis group, coupled toa close working relationship between Drug Metabolism and Medicinal Chemistry, representsa framework within which this perspective becomes viable; the overall aim is to bring saferdrugs to patients.