Epithelial transport of drugs in cell culture. II: Effect of extracellular calcium concentration on the paracellular transport of drugs of different lipophilicities across monolayers of intestinal epithelial (Caco-2) cells.

A human intestinal cell line, Caco-2, was used as a model to study the passive diffusion of a homologous series of drugs (beta-blocking agents) of different lipophilicity across intestinal epithelium. The permeability of the Caco-2 monolayers was modulated by the use of a calcium switch assay. The transmembrane resistance could be reversibly decreased from approximately 280 ohms.cm2 (a resistance similar to that of colon epithelium) to approximately 60 ohms.cm2 (a resistance similar to that of small intestine epithelium). Transmission electron microscopy showed that the increased electrical permeability was caused by a reversible separation of the components of the junctional complex and not by cell detachment. In general, the increased paracellular permeability resulted in a 2- to 9-fold increase in the apparent permeability coefficients for the more hydrophilic drugs (e.g., from 0.20 +/- 0.010 x 10(-6) to 1.43 +/- 0.185 x 10(-6) cm/s for atenolol), while the transport parameters for the more lipophilic drugs remained unchanged (e.g., 43.03 +/- 3.64 x 10(-6) and 46.10 +/- 3.25 x 10(-6) cm/s for propranolol). These findings indicate that it is possible to study the contribution of the paracellular pathway to the transport of drugs in the Caco-2 model.