Li Albert P
Advanced Pharmaceutical Sciences Inc., Columbia, Maryland 21045, USA.
ALTEX. 2008;25(1):33-42. doi: 10.14573/altex.2008.1.33.
Human-based in vitro hepatic experimental systems are now used routinely in drug development. The rationale for the use of human-based in vitro systems is based on the known species-species differences in drug properties. Human-specific drug properties, by definition, cannot be defined using nonhuman experimental animals, and therefore can only be assessed in the preclinical phase of drug development using in vitro human-based approaches. A widely applied human-based in vitro experimental system for preclinical evaluation of drug properties is human hepatocytes. Our laboratory was one of the first to successfully isolate highly viable and functional hepatocytes from human livers, and we recently developed cryopreservation procedures to retain high viability and high attachment efficiency of the isolated hepatocytes. Successful cryopreservation of human hepatocytes greatly enhances the utility of this valuable in vitro experimental system, allowing storage, transport, convenient scheduling of experimentation and repeat experimentation using hepatocytes isolated from the same donors. Effective assays have been developed with cryopreserved human hepatocytes using multiwell plates for the evaluation of critical drug properties, including metabolic stability, drug-drug interaction potential, and drug toxicity. Human hepatocytes represent an alternative experimental system that plays a significant role in the 3Rs - the reduction, refinement, and replacement of the use of animals in preclinical drug development research.
基于人体的体外肝脏实验系统如今在药物研发中被常规使用。使用基于人体的体外系统的基本原理是基于已知的药物特性在物种间的差异。根据定义，人类特有的药物特性无法通过非人类实验动物来确定，因此只能在药物研发的临床前阶段使用基于人体的体外方法进行评估。一种广泛应用于药物特性临床前评估的基于人体的体外实验系统是人类肝细胞。我们的实验室是最早成功从人类肝脏中分离出高活力和功能性肝细胞的实验室之一，并且我们最近开发了冷冻保存程序以保持分离出的肝细胞的高活力和高贴壁效率。人类肝细胞的成功冷冻保存极大地提高了这个有价值的体外实验系统的实用性，允许对从同一供体分离出的肝细胞进行储存、运输、方便地安排实验时间以及重复实验。已经开发出了使用多孔板对冷冻保存的人类肝细胞进行有效检测的方法，用于评估关键的药物特性，包括代谢稳定性、药物相互作用潜力和药物毒性。人类肝细胞代表了一种替代实验系统，在3R原则（即减少、优化和取代临床前药物研发研究中动物的使用）中发挥着重要作用。
