EPITHELIAL TRANSPORT OF DRUGS IN CELL-CULTURE .2. 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 (β‐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 ∼280 ohms · cm2 (a resistance similar to that of colon epithelium) to ∼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 × 10−6 to 1.43 ± 0.185 × 10−6 cm/s for atenolol), while the transport parameters for the more lipophilic drugs remained unchanged (e.g., 43.03 ± 3.64 × 10−6 and 46.10 ± 3.25 × 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. Copyright © 1990 Wiley‐Liss, Inc., A Wiley Company