Gross Cindy J, Kramer Jeffrey A
Pharmacia Corporation, Mail Stop TA1, 800 North Lindbergh Blvd, St Louis, MO 63167, USA.
Expert Opin Drug Saf. 2003 Mar;2(2):147-59. doi: 10.1517/14740338.2.2.147.
Molecular toxicology, the application of molecular biology principles and technologies to preclinical safety assessment, represents a key tool for understanding mechanisms of toxicity and assessing the risks associated with specific toxicities. The application of gene expression markers to early stage preclinical safety assessment has the potential to impact pipelines in two main areas: lead optimisation and issue management. Lead optimisation focuses on deprioritising leads with significant, development-limiting toxicological liabilities while advancing those compounds with the greatest chance of successfully navigating the gauntlet of preclinical and clinical safety studies. Issue management utilises mechanistic toxicology studies to position non-development-limiting findings prior to the onset of Good Laboratory Practice studies in full development, and can help to identify and validate gene expression markers predictive of adverse events to avoid issues in second-generation projects. In this review, the authors describe the application of molecular toxicology to a standard pharmaceutical testing funnel, provide examples of the successful application of gene expression markers, and discuss the potential for future impact in several broad categories of clinically relevant toxicity.
分子毒理学，即将分子生物学原理和技术应用于临床前安全性评估，是理解毒性机制和评估特定毒性相关风险的关键工具。基因表达标志物在临床前早期安全性评估中的应用有可能在两个主要领域影响研发流程：先导化合物优化和问题管理。先导化合物优化侧重于排除具有重大、限制研发的毒理学风险的先导化合物，同时推进那些最有可能成功通过临床前和临床安全性研究重重考验的化合物。问题管理利用机制毒理学研究，在全面开展的良好实验室规范研究开始之前，对不限制研发的研究结果进行定位，并有助于识别和验证预测不良事件的基因表达标志物，以避免在第二代项目中出现问题。在本综述中，作者描述了分子毒理学在标准药物测试流程中的应用，提供了基因表达标志物成功应用的实例，并讨论了其在几大类临床相关毒性方面未来产生影响的可能性。
