Nassar Alaa-Eldin F, Lopez-Anaya Arturo
Wyeth Research, Department of Drug Metabolism, 500 Arcola Road, Collegeville, PA 19426, USA.
Curr Opin Drug Discov Devel. 2004 Jan;7(1):126-36.
Idiosyncratic drug reactions (IDRs; a specific type of drug toxicity characterized by delayed onset) are a major complication of drug therapy that need to be addressed during drug discovery and development. Efforts to improve drug safety are hampered by the lack of an accepted approach to predict IDRs, which in turn is due to the low incidence of occurrence of IDRs and the various potential mechanisms involved in these reactions. The concept of the relative rarity and formation of reactive metabolite of IDRs is briefly described. Hypothetical chemical mechanisms for the formation of reactive metabolites are summarized, including a classification of adverse drug reactions and types of reactive metabolites. The relative merits of current and potential strategies for dealing with reactive intermediates in drug discovery and development are examined, and the significance of covalent binding in drug discovery/development in vitro and in vivo systems is considered. Also discussed are the merits of tools (screening methods to trap reactive intermediates, enzyme inhibition and covalent binding) and strategies for predicting which new drugs have the potential to produce reactive intermediates and IDRs; these approaches may be considered to have the potential to improve the overall safety profile of drug candidates at various stages of the drug discovery and development process.
特异质药物反应（IDRs；一种以延迟发生为特征的特定类型的药物毒性）是药物治疗的主要并发症，在药物发现和开发过程中需要加以解决。由于缺乏预测IDRs的公认方法，改善药物安全性的努力受到阻碍，而这又是由于IDRs的发生率较低以及这些反应涉及多种潜在机制所致。本文简要描述了IDRs相对罕见以及反应性代谢产物形成的概念。总结了反应性代谢产物形成的假设化学机制，包括药物不良反应的分类和反应性代谢产物的类型。研究了在药物发现和开发中处理反应性中间体的当前和潜在策略的相对优点，并考虑了共价结合在体外和体内药物发现/开发系统中的意义。还讨论了工具（捕获反应性中间体的筛选方法、酶抑制和共价结合）的优点以及预测哪些新药有可能产生反应性中间体和IDRs的策略；这些方法可能被认为有潜力在药物发现和开发过程的各个阶段改善候选药物的整体安全性。
