Improving the intestinal mucosal cell uptake of water insoluble compounds

A significant increase in intestinal mucosal cell uptake rate can be achieved by making brush border enzyme-labile derivatives of water insoluble compounds. The test compounds chosen were decanol, hexadecanol, their corresponding lysinate esters, hydrocortisone and its phosphate and succinate esters. Intestinal perfusion and intestinal ring uptake experiments in the alcohol study demonstrated that prodrug uptake was comparable to uptake of the free alcohol below the solubility of the parent compound; i.e., there was little or no loss in intestinal permeability. Prodrug uptake continued to increase linearly above the solubility of the free alcohol in the ring system. Similar results were obtained for hydrocortisone and its prodrugs when uptake was examined in the intestinal ring system; furthermore, rapid post-incubation freezing of the tissue coupled with an HPLC assay capable of separating drug from prodrug permitted determination of the species absorbed. In all cases, only free alcohol was detected in the tissue. Histological studies verified the integrity of intestinal tissue under experimental conditions. The in vitro technique is advantageous for screening drug absorption. The very substantial potential of this prodrug approach is demonstrated in particular with hexadecanol and hexadecyl lysinate, where the uptake rate of the prodrug was four orders of magnitude greater than that of the free alcohol.