Hurel Corporation, Beverley Hills, California, CA, USA.
Biochem Pharmacol. 2010 Apr 1;79(7):1036-44. doi: 10.1016/j.bcp.2009.11.010. Epub 2009 Nov 27.
Within the global pharmaceutical and biotech industries, there is significant interest in identifying in vitro screening systems that are more human-relevant-i.e., that offer greater utility in predicting subcellular and cellular physiological responses in humans in vivo-and that thereby allow investigators to reduce the incidence of costly late-stage failures during pharmaceutical clinical trials, as well as to reduce the use of animals in drug testing. Currently incumbent in vitro screening methods, such as culturing human hepatocytes in suspension, while useful, are limited by a lack of long term cellular function. In order to address this limitation, we have established an integrated, microfluidic, in vitro platform that combines the patented HmuREL((R)) microdevice with a hepatic coculture system. In the present report, we use this platform to study clearance and metabolite generation of a battery of molecular entities. The results show that the flow-based coculture system is capable of clearing, with improved resolution and predictive value, compounds with high, medium, and low clearance values. In addition, when coculture is coupled with flow, higher metabolite production rates are obtained than in static systems.
在全球制药和生物技术行业中，人们对发现更具人类相关性的体外筛选系统（即，在预测体内人类细胞和亚细胞生理反应方面提供更大的效用）产生了浓厚的兴趣，从而使研究人员能够降低药物临床试验中昂贵的后期失败率，并减少药物测试中对动物的使用。目前使用的体外筛选方法，如悬浮培养人肝细胞，虽然有用，但由于缺乏长期的细胞功能而受到限制。为了解决这一限制，我们建立了一个集成的微流控体外平台，将专利的 HmuREL((R))微器件与肝共培养系统相结合。在本报告中，我们使用该平台研究了一系列分子实体的清除和代谢产物生成。结果表明，基于流动的共培养系统能够以更高的分辨率和预测价值清除具有高、中、低清除值的化合物。此外，当共培养与流动相结合时，可获得比静态系统更高的代谢产物生成速率。
