Salerno Simona, Bartolo Loredana De
Institute on Membrane Technology, National Research Council of Italy, ITM-CNR, c/o University of Calabria, cubo 17/C, Via P. Bucci, I-87030 Rende (CS). Italy.
Curr Pharm Des. 2017;23(2):319-327. doi: 10.2174/1381612822666161025155616.
In drug development, in vitro human model systems are absolutely essential prior to the clinical trials, considering the increasing number of chemical compounds in need of testing, and, keeping in mind that animals cannot predict all the adverse human health effects and reactions, due to the species-specific differences in metabolic pathways. The liver plays a central role in the clearance and biotransformation of chemicals and xenobiotics. In vitro liver model systems by using highly differentiated human cells could have a great impact in preclinical trials. Membrane biohybrid systems constituted of human hepatocytes and micro- and nano-structured membranes, represent valuable tools for studying drug metabolism and toxicity. Membranes act as an extracellular matrix for the adhesion of hepatocytes, and compartmentalise them in a well-defined physical and chemical microenvironment with high selectivity. Advanced 3-D tissue cultures are furthermore achieved by using membrane bioreactors (MBR), which ensure the continuous perfusion of cells protecting them from shear stress. MBRs with different configurations allow the culturing of cells at high density and under closely monitored high perfusion, similarly to the natural liver. These devices that promote the long-term maintenance and differentiation of primary human hepatocytes with preserved liver specific functions can be employed in drug testing for prolonged exposure to chemical compounds and for assessing repeated-dose toxicity. The use of primary human hepatocytes in MBRs is the only system providing a faster and more cost-effective method of analysis for the prediction of in vitro human drug metabolism and enzyme induction alternative and/or complementary to the animal experimentation. In this paper, in vitro models for studying drug metabolism and toxicity as advanced biohybrid membrane systems and MBRs will be reviewed.
在药物研发中，鉴于需要测试的化合物数量不断增加，且考虑到由于代谢途径存在物种特异性差异，动物无法预测所有对人类健康的不良影响和反应，因此体外人体模型系统在临床试验之前绝对至关重要。肝脏在化学物质和外源性物质的清除及生物转化过程中起着核心作用。利用高度分化的人类细胞构建的体外肝脏模型系统可能会对临床前试验产生重大影响。由人类肝细胞与微纳结构膜组成的膜生物杂交系统，是研究药物代谢和毒性的宝贵工具。膜作为肝细胞黏附的细胞外基质，并以高选择性将它们分隔在明确的物理和化学微环境中。此外，通过使用膜生物反应器（MBR）可实现先进的三维组织培养，该反应器能确保细胞持续灌注，保护它们免受剪切应力影响。具有不同配置的MBR允许在高密度和密切监测的高灌注条件下培养细胞，类似于天然肝脏。这些促进原代人类肝细胞长期维持和分化并保留肝脏特定功能的装置，可用于药物测试，以评估长时间接触化合物的情况以及重复给药毒性。在MBR中使用原代人类肝细胞是唯一一种能提供更快且更具成本效益的分析方法的系统，用于预测体外人类药物代谢和酶诱导，可替代和/或补充动物实验。本文将对作为先进生物杂交膜系统和MBR的用于研究药物代谢和毒性的体外模型进行综述。
