HIGH LIPOPHILICITY DECREASES DRUG TRANSPORT ACROSS INTESTINAL EPITHELIAL-CELLS

It is generally admitted in drug research that the passage of molecule s across cellular barriers increases with lipophilicity and that the m ost lipophilic compounds will have the highest intestinal absorption. Using two in vitro models of intestinal epithelium, we presently demon strate that this concept is not always valid and that highly lipophili c compounds display a low transepithelial permeability. We used epithe lial cell lines grown on permeable filters to measure in vitro the tra nsepithelial permeability of various molecules. The octanol/buffer dis tribution coefficient of the drugs (D-o/b) was taken as an index of li pophilicity. When log D-o/b values were lower than 3.5, the transepith elial permeability coefficient increased with the lipophilicity. But f or log D-o/b values ranging from 3.5 to 5.2, the transepithelial perme ability coefficient decreased with increasing lipophilicity. Identical results were observed with two differentiated intestinal epithelial c ell lines (HT29-18-C-1 and Caco-2) and in unstirred or agitated condit ions. The results show that an octanol/buffer distribution coefficient value around 3000 corresponds to an optimal transepithelial passage o f drugs and that too high a lipophilicity can result in low intestinal epithelial permeability and in low oral absorption.