THE HUMAN INTESTINAL EPITHELIAL-CELL LINE CACO-2 - PHARMACOLOGICAL AND PHARMACOKINETIC APPLICATIONS

The gastrointestinal tract remains the most popular and acceptable rou te of administration for drugs. It offers the great advantage of conve nience and many compounds are well absorbed and thereby provide accept able plasma concentration-time profiles. Currently there is considerab le interest from the pharmaceutical industry in development of cell cu lture systems that would mimic the intestinal mucosa in order to evalu ate strategies for investigating and/or enhancing drug absorption. The intestinal epithelial cells of primary interest, from the standpoint of drug absorption and metabolism, are the villus cells, which are ful ly differentiated cells. An in vitro cell culture system consisting of a monolayer of viable, polarized and fully differentiated villus cell s, similar to that found in the small intestine, would be a valuable t ool in the study of drug and nutrient transport and metabolism. The Ca co-2 cell line, which exhibits a well-differentiated brush border on t he apical surface and tight junctions, and expresses typical small-int estinal microvillus hydrolases and nutrient transporters, has proven t o be the most popular in vitro model (a) to rapidly assess the cellula r permeability of potential drug candidates, (b) to elucidate pathways of drug transport (e.g., passive versus carrier mediated), (c) to ass ess formulation strategies designed to enhance membrane permeability, (d) to determine the optimal physicochemical characteristics for passi ve diffusion of drugs, and (e) to assess potential toxic effects of dr ug candidates or formulation components on this biological barrier. Si nce differentiated Caco-2 cells express various cytochrome P450 isofor ms and phase II enzymes such as UDP-glucuronosyltransferases, sulfotra nsferases and glutathione-S-transferases, this model could also allow the study of presystemic drug metabolism.