Intestinal absorption of drugs: digitalis binding and transport by brush-border membrane vesicles from human duodenum

The intestinal epithelial cell layer is the first major barrier to absorption encountered by xenobiotics. An understanding of the mechanism and sites of drug absorption and metabolism is thus a critical first step in developing orally active compounds. In this context human brush-border membrane vesicles obtained from multi-organ donor intestines have been purified. This model has been validated and used to investigate the duodenal absorption of drugs "in vitro", namely digitalis. It is well established that digitalis compounds present great variability in their respective "in vivo" bioavailability in human (60-90% for digoxin, 0% for ouabain). These particular characteristics prompted us to determine whether this membrane model constitutes a suitable tool in predicting the bioavailability or intestinal transport processes of these molecules. The uptake of [3H] digoxin and [3H] ouabain by membrane vesicles incubated in media of increasing osmolarities demonstrated that: i/two factors are involved in the uptake processes of digoxin: membrane binding and intravesicular transport (osmotic sensitive), ii/ for ouabain, no osmotic sensitivity was observed, indicating that no transport process occurred, but only membrane binding processes. These results are in complete agreement with the absolute bioavailability data reported for man "in vivo". This human brush-border model constitutes an interesting approach to the intestinal absorption phenomena which are known to be among the factors influencing the bioavailability of orally administered drugs.