High Throughput Liver Toxicity Screening

描述（由申请人提供）：肝毒性是新药开发失败的最常见原因，除疗效失败外。为了解决这个问题，我们开发了一系列测试，使用一种获得专利的人类肝细胞系：增殖来测量细胞毒性的基本事件。ATP含量，半胱天冬酶激活和乳酸脱氢酶释放。此外，我们还采用了几种与肝脏药物代谢特异性相关的试验：cypal /1A2诱导、cyp3A4诱导和p -糖蛋白抑制。当联合使用时，这7种测试提供了肝脏中化合物相互作用的广泛而丰富的图像。它们速度快，坚固耐用，价格便宜。在这个项目的第一阶段，我们建议筛选一个小的（640）随机选择的化合物库和一组结构相关的化合物（NSAIDS）来检查该系统的反应广度。如果初步筛选的结果令人满意，在第二阶段，我们将建议筛选大量随机化合物（约30,000）和较小的结构相关化合物系列，并建立一个可用于指导新药合成的毒性数据库。

DESCRIPTION (provided by applicant): Liver toxicity is the most common cause for failure in new drug development except for efficacy failures. To address this problem, we have developed a series of tests measuring basic events in cellular toxicity using a patented human liver cell line: proliferation. ATP content, caspase activation and lactate dehydrogenase release. In addition, we have employed several tests that are specifically related to drug metabolism in the liver: cyplAl/1A2 induction cyp3A4 induction and P-glycoprotein inhibition. When used in combination, these seven tests give a broad and rich picture of compound interaction in the liver. They are fast, rugged and inexpensive. In phase I of this project, we propose to screen a small (640) library of randomly chosen compounds and a group of structurally related compounds (NSAIDS) to examine the breadth of response of this system. If the results of this preliminary screening are satisfactory, in phase II we would propose to screen a large series of random compounds (approximately 30,000) and smaller series of structurally related compounds with the idea of building a database of toxicity that could be used to guide new drug synthesis. PROPOSED COMMERCIAL APPLICATIONS: ACTIVTox, our human liver toxicity and metabolism system, is based on a patented human liver cell line and proprietary medium and cell culture conditions. We expected to sell kits consisting of ready to use plates filled with cells, medium and reagents to carry out the individual test on a high throughput basis. The market for such a human toxicity system exceeds $25 million annually.