Dynamics and Metabolism Department, Pfizer Global Research & Development, Groton, CT 06340, USA.
Expert Rev Clin Pharmacol. 2008 Jul;1(4):515-31. doi: 10.1586/17512433.1.4.515.
It is generally accepted that bioactivation of relatively inert functional groups (toxicophores) to reactive metabolites is an obligatory step in the pathogenesis of certain idiosyncratic adverse drug reactions (IADRs). IADRs cannot be detected in regulatory animal toxicity studies and, given their low frequency of occurrence in humans (1 in 10,000 to 1 in 100,000), they are often not detected until the drug has gained broad exposure in a large patient population. The detection of IADRs during late clinical trials or after a drug has been released can lead to an unanticipated restriction in its use, and even in its withdrawal. To date, there is neither a consistent nor a well-defined link between bioactivation and IADRs; however, the potential does exist for these processes to be causally related. Thus, the formation of reactive metabolites with a drug candidate is generally considered a liability in most pharmaceutical companies. Procedures have been implemented to evaluate bioactivation potential of new drug candidates with the goal of eliminating or minimizing reactive metabolite formation by rational structural modification of the lead chemical class. While such studies have proven extremely useful in the retrospective analysis of bioactivation pathways of toxic drugs and defining toxicophores, their ability to accurately predict the IADR potential of new drug candidates has been challenged, given that several commercially successful drugs form reactive metabolites, yet, they are not associated with a significant incidence of IADRs. In this article, we review the basic methodology that is currently utilized to evaluate the bioactivation potential of new compounds, with particular emphasis on the advantages and limitation of these assays. Plausible reasons for the excellent safety record of certain drugs susceptible to bioactivation are also explored. Overall, these observations provide valuable guidance in the proper use of bioactivation assessments when selecting drug candidates for development.
人们普遍认为，将相对惰性的官能团（毒力基团）生物转化为反应性代谢物是某些特发性药物不良反应（IADR）发病机制中的必要步骤。在监管动物毒性研究中无法检测到 IADR，并且由于其在人类中的发生率较低（每 10,000 至 100,000 人中有 1 例），因此通常在药物在大量患者人群中广泛使用后才会发现。在后期临床试验中或药物发布后发现 IADR 可能会导致其使用受到意外限制，甚至被撤回。迄今为止，生物转化与 IADR 之间既没有一致的联系，也没有明确的定义；然而，这些过程存在因果关系的可能性。因此，候选药物的反应性代谢物的形成通常被大多数制药公司视为不利因素。已经实施了程序来评估新候选药物的生物转化潜力，以期通过合理的结构修饰来消除或最小化先导化学物质的反应性代谢物形成。虽然这些研究在回顾性分析有毒药物的生物转化途径和定义毒力基团方面已被证明非常有用，但它们准确预测新候选药物的 IADR 潜力的能力受到了挑战，因为一些商业成功的药物形成了反应性代谢物，但它们与 IADR 的发生率没有显著关联。在本文中，我们回顾了目前用于评估新化合物生物转化潜力的基本方法，特别强调了这些测定方法的优点和局限性。还探讨了某些易发生生物转化的药物具有出色安全性记录的合理原因。总的来说，这些观察结果为在选择候选药物进行开发时正确使用生物转化评估提供了有价值的指导。
