In vitro assays developed for the evaluation of drug-like properties can accelerate the drug development process. The key assays are those for the evaluation of bioavailability, metabolic stability, drug-drug interaction potential, and toxicity. For bioavailability, the human colon carcinoma derived Caco-2 assay is the most widely used, allowing the evaluation of multiple pathways of intestinal absorption including paracellular uptake, transcellular uptake, and transporter-mediated uptake and efflux. For metabolic stability and drug-drug interactions, human liver microsomes, hepatocytes, and cDNA-expressed microsomes are commonly used, with human hepatocytes representing the most complete system, containing all metabolic enzymes and cofactors at physiological level and an intact plasma membrane to allow the modeling of intracellular drug concentrations. Primary human cells from target organs (e.g., human hepatocytes for human hepatotoxicity) should represent the best experimental system for the evaluation of human drug toxicity. These assays, when applied intelligently with their limitations, should greatly facilitate the selection of drug candidates with a high probability of clinical success.
Keywords: ADMET, enzymes, microsomes, hepatocytes, hepatotoxicity