Li Albert P
In Vitro ADMET Laboratories LLC and Advanced Pharmaceutical Sciences Inc., 9221 Rumsey Road, Suite 8, Columbia, MD 21045, USA.
Curr Drug Saf. 2007 Sep;2(3):193-9. doi: 10.2174/157488607781668909.
Accurate prediction of human drug safety remains a major challenge for drug development. Species-difference in drug toxicity represents a main reason for the difficulty in the prediction of human drug toxicity with nonhuman animal models. A combined in vitro-in vivo strategy (IVIVS), using human-based in vitro experimental systems to derive human-specific information, and animal systems for in vivo variables, may lead to a more accurate prediction of human in vivo drug toxicity. The success of IVIVS requires in vitro models with human-specific drug metabolism, appropriate target cell populations, and relevant endpoints. A novel theory, the Target Cell Initiation Theory for drug-induced organ failure (TACIT), is proposed to support the IVIVS. Based on TACIT, toxicity that requires chronic administration and multiple secondary changes may be defined by the evaluation of changes in target cells that initiate the cascade of secondary events. A novel in vitro experimental system, the Integrated Discrete Multiple Organ Co-culture (IdMOC) system, which allows the evaluation of multiple organ toxicity under conditions allowing multiple organ interactions, is described as a promising technology.
准确预测人类药物安全性仍然是药物研发中的一项重大挑战。药物毒性的物种差异是使用非人类动物模型预测人类药物毒性困难的主要原因。一种体外-体内联合策略（IVIVS），利用基于人类的体外实验系统获取人类特异性信息，并利用动物系统研究体内变量，可能会更准确地预测人类体内药物毒性。IVIVS的成功需要具有人类特异性药物代谢、合适的靶细胞群体和相关终点的体外模型。本文提出了一种新理论——药物诱导器官衰竭的靶细胞启动理论（TACIT），以支持IVIVS。基于TACIT，需要长期给药和多次继发变化的毒性可通过评估引发继发事件级联反应的靶细胞变化来定义。一种新型体外实验系统——整合离散多器官共培养（IdMOC）系统，它能够在允许多器官相互作用的条件下评估多器官毒性，被描述为一项很有前景的技术。
