Nelson S D
School of Pharmacy, University of Washington, Seattle 98195-7631, USA.
Adv Exp Med Biol. 2001;500:33-43. doi: 10.1007/978-1-4615-0667-6_4.
This chapter provides just a few newer examples of structural moieties found in drugs that have been associated with reactive metabolite formation and toxicities. For a discussion of several other structures in drugs that undergo metabolic activation to reactive intermediates, the reader is directed to previous volumes in this series and other chapters in this book, as well as a previous condensed review (Nelson, 1982). Since that review, some new knowledge allows us to better predict that some structural moieties are more likely than others to form drug reactive metabolites that may be involved in causing toxic effects in humans. For example, most aniline-, thiophene-, and nitroaromatic-containing drugs have had a relatively high incidence of adverse effects, and it would be prudent in the drug discovery process to avoid these substructures if possible. However, as illustrated by the case of olanzapine, these structures may be important for potent activity, and could therefore be beneficial in some cases. The glitazones represent a new class of drugs with a unique thiazolidinedione structure. This raises two important points. First, it demonstrates how limited our knowledge base is in regard to structure toxicity relationships when new structures are introduced. Our approaches must be very empirical and are far from quantitative for the reasons outlined in the introduction. Secondly, the glitazones point out the importance of benefit/risk considerations. This was a new structural class of drugs with a unique spectrum of action that is very beneficial in the treatment of a major disease. Despite some suspected risk of toxicity, based on early trials, troglitazone was approved for use with careful monitoring. This author believes that was the right decision, as was the decision to withdraw the drug when the risk became unacceptable, especially with the introduction of safer alternatives. If this were just another NSAID (e.g., bromfenac), there would be little reason for approval. In summary, as I pointed out previously (Nelson, 1982), with our limited knowledge of structure toxicity relationships, we can only make reasonable judgments as to risk assessment of a new drug in humans, and hope that we neither release a dangerous chemical entity nor, as importantly, abort an effective one.
本章仅提供了一些在药物中发现的结构部分的较新示例，这些结构与活性代谢物的形成及毒性有关。关于药物中其他几种经代谢活化生成活性中间体的结构的讨论，读者可参考本系列的前几卷、本书的其他章节以及之前的一篇简要综述（纳尔逊，1982年）。自那篇综述发表以来，一些新知识使我们能够更好地预测，某些结构部分比其他部分更有可能形成可能导致人体毒性作用的药物活性代谢物。例如，大多数含苯胺、噻吩和硝基芳烃的药物不良反应发生率相对较高，因此在药物研发过程中，若有可能应避免这些亚结构。然而，如奥氮平的例子所示，这些结构对于强效活性可能很重要，因此在某些情况下可能是有益的。格列酮类代表了一类具有独特噻唑烷二酮结构的新型药物。这引出了两个要点。首先，它表明当引入新结构时，我们关于结构-毒性关系的知识基础是多么有限。由于引言中所述的原因，我们的方法必须非常经验性，且远非定量的。其次，格列酮类指出了效益/风险考量的重要性。这是一类具有独特作用谱的新型结构药物，在治疗一种主要疾病方面非常有益。尽管基于早期试验存在一些毒性风险的怀疑，但曲格列酮在仔细监测下被批准使用。作者认为这是正确的决定，当风险变得不可接受时，尤其是有了更安全的替代药物时，将该药物撤市的决定也是正确的。如果这只是另一种非甾体抗炎药（如溴芬酸），那么批准的理由就很少了。总之，正如我之前指出的（纳尔逊，1982年），鉴于我们对结构-毒性关系的了解有限，我们只能对新药在人体中的风险评估做出合理判断，并希望我们既不释放危险的化学实体，同样重要的是，也不放弃有效的药物。
