Animal models of human disease in drug safety assessment.
Animal models of human disease in drug safety assessment.
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DOI：
10.2131/jts.28.109
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发表时间：
2003-08-01
期刊：
影响因子：
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通讯作者：
Boelsterli, Urs A
中科院分区：
文献类型：
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作者：
Boelsterli, Urs A
人类疾病的动物模型已广泛用于药物发现，但很少用于毒理学研究和筛选（致癌性试验中的转基因模型除外）。尽管与特定疾病相关的遗传和/或获得性病理生理学改变可能会大大加剧某些患者亚群对药物的毒性反应，但这些既存病理状况通常不会在临床前安全性评估中考虑。易感性的疾病相关决定因素的实例包括促炎性病症中细胞因子网络的破坏、某些神经退行性疾病中的线粒体改变和氧化应激、某些病毒感染中的抗氧化防御改变以及2型糖尿病中的基因表达改变和线粒体功能障碍。因此，如果由药物或代谢物引起的细胞应激和疾病相关效应叠加，则个体可能对潜在的药物毒性敏感。适度炎症的动物模型确实可以增强某些药物的毒性。类似地，2型糖尿病的啮齿动物模型使动物易受噻唑烷二酮类抗糖尿病药物的肝毒性作用的影响。总之，它建议，定制和简化的模型，通过和越来越多地使用，尽管有明显的局限性，作为卫星毒性研究的最佳基板，以促进候选人的选择，帮助预测罕见和意外的毒性，并确定新的生物标志物。
Animal models of human disease have been widely used in drug discovery, but they are rarely utilized in toxicological research and screening (except for transgenic models in carcinogenicity testing). Although genetic and/or acquired pathophysiological alterations associated with a particular disease may greatly exacerbate toxic responses to drugs in certain patient subsets, these pre-existing pathological conditions are usually not considered in preclinical safety assessment. Examples of disease-related determinants of susceptibility include disruption of the cytokine network in pro-inflammatory conditions, mitochondrial alterations and oxidative stress in certain neurodegenerative diseases, altered antioxidant defense in certain viral infections, and altered gene expression and mitochondrial dysfunction in type 2 diabetes. Hence, if cellular stress caused by drugs or metabolites and the disease-related effects are superimposed, then an individual can become sensitized to potential drug toxicity. Animal models of modest inflammation indeed can potentiate the toxicity of certain drugs. Similarly, rodent models of type 2 diabetes predispose the animals to hepatotoxic effects of thiazolidinediones antidiabetics. In conclusion, it is suggested that tailor-made and simplified models be adopted and increasingly used, in spite of clear limitations, as optimal substrates for satellite toxicity studies to facilitate candidate selection, help predict rare and unexpected toxicity, and identify new biomarkers.