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.
Thesaurus Terms: cytochrome P450, drug metabolism, drug screening /evaluation, hepatotoxin, high throughput technology, liver pharmacology, technology /technique development, toxicant screening adenosine triphosphate, cell proliferation, cysteine endopeptidase, lactate dehydrogenase, nonsteroidal antiinflammatory agent tissue /cell culture
