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A n evolving union of high throughput screening (HTS) and absorption, distribution, metabolism, excretion, and toxicology (ADMET) technologies have transformed drug discovery. Human tissue-based, in vitro ADMET assays can efficiently generate reliable profiles for structure-activity or structure-property relationships of compounds from screening ''hit sets'' or libraries. The process of identifying discovery compounds with desirable ''druglike'' properties has consequently become increasingly data-driven. Chemists and biologists initiate the process by submitting requests to our laboratory through an intranet database. A Caco-2 cell model, automated on a Tecan Genesis workstation, evaluates the intestinal absorption of drug candidates. Distribution properties are determined with a high-throughput equilibrium dialysis technique for measuring plasma protein binding. Drug metabolism can be evaluated on a Genesis workstation via measurements of metabolic stability in liver microsomes. Drug-drug interactions can be predicted with HTS techniques using human recombinant hepatic CYP450 isoforms. A Genesis workstation, integrated with a fluorescence plate reader, executes CYP450 inhibition assays. Cell toxicity assays using human hepatocytes can serve as early, high-throughput indicators of potential systemic drug toxicity. The early availability of ADMET profiling data can now enable discovery scientists to quickly evaluate the factors that influence the pharmacodynamic and pharmacokinetic properties of compounds in lead optimization.

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