药物代谢诱导毒性的体外预测方法研究进展  

Research progress in in vitro methods for prediction of drug metabolism-induced toxicity

作　　者：孙亚奇 陆启荣[1,2,3] 刘爱梅 刘振利[1,2,3] 王旭 潘源虎[1,2,3] 袁宗辉[1,2,3] SUN Ya-qi;LU Qi-rong;LIU Ai-mei;LIU Zhen-li;WANG Xu;PAN Yuan-hu;YUAN Zong-hui(College of Veterinary Medicine,Huazhong Agricultural University,Wuhan 430070,China;National Reference Laboratory of Veterinary Residues,Huazhong Agricultural University,Wuhan 430070,China;Ministry of Agriculture and Rural Affairs Key Laboratory for the Detection of Veterinary Drug Residues in Foods,Huazhong Agricultural University,Wuhan 430070,China)

机构地区：[1]华中农业大学动物医学院,湖北武汉430070 [2]华中农业大学国家兽药残留基准实验室,湖北武汉430070 [3]华中农业大学农业农村部食品兽药残留检测重点实验室,湖北武汉430070

出　　处：《中国药理学与毒理学杂志》2019年第11期1000-1006,共7页Chinese Journal of Pharmacology and Toxicology

基　　金：国家重点研发计划资助(2018YFD0501405)。

摘　　要：药物代谢诱导的毒性反应是导致候选化合物在药物开发中失败的一个主要原因,建立简便、快速、准确的毒性预测方法是毒理学研究的重点之一。本文对由药物代谢物诱导的毒性体外预测方法进行综述,主要包括计算毒理学方法、肝样细胞模型、高通量芯片模型和三维细胞培养法等。计算毒理学基于计算机技术、生物信息学以及现有的实验数据对先导化合物和候选药物对人体产生的代谢毒性进行预测,它能缩短研发周期,降低开发成本,提高新药开发成功率,但高度依赖于现有的实验数据。高通量芯片技术利用生物化学以及细胞培养技术对一系列化合物的生物活性进行筛选和检测,此模型目前还处于初级阶段,还需继续进行深入研究。三维细胞模型可模拟体内细胞的生长微环境,很好地表现出细胞在体内的生理状态,尤其是对中空纤维三维生物反应器以及器官芯片系统技术的开发,使得体外预测药物代谢与毒性更加准确真实,但需要在细胞活力和稳定性、关键代谢以及信号通路等方面对平台进行比较。基于计算毒理学方法、肝样细胞模型、高通量芯片模型和三维细胞培养等模型的研究将为代谢物毒性体外预测提供参考。Drug metabolism-induced toxicity is one of the main causes of the failure of candidate compounds in drug development.Establishing a simple,rapid and accurate method for predicting toxicity is one of the priorities of toxicology research.This article reviews the in vitro prediction methods for drug metabolism-induced toxicity,including in silico toxicology method,hepatocyte-like cell models,high-throughput chip model and three dimension cell culture.The in silico toxicology method predicts the metabolic toxicity of lead compounds and candidate drugs to humans based on computer technology,bioinformatics,and existing experimental data.It can short the development cycle,reduce costs of develop?ment and increase the success rate of new drug development.But it is highly dependent on the existing experimental data.High-throughput chip technology uses biochemistry and cell culture technology to screen and detect the biological activities of a series of compounds.This model is currently in its infancy and further research is needed.The three-dimensional cell model can simulate the growth microenvi?ronment of cells in the body,which shows the physiological state of the cells in the body,especially the development of hollow fiber three-dimensional bioreactor and organ chip system technology,which makes the prediction of drug metabolism and toxicity in vitro more accurate and real.However,the plat?forms need to be compared in terms of cell viability and stability,key metabolisms,and signaling path?ways.Studies based on the in silico toxicology method,hepatocyte-like cell models,high-throughput chip model and three dimension cell culture model will provide reference for in vitro prediction of metab?olite toxicity.

关 键 词：药物 代谢 毒性 体外 预测方法 

分 类 号：R965[医药卫生—药理学]