Improving the Intestinal Absorption of Water-Insoluble Compounds and the Specificity of Targeted Drug Delivery.

Abstract

The problems of poor drug absorption after oral administration and of site-specific drug delivery have received a great deal of recent attention. This research presents a multi-disciplinary approach to these problems that incorporates physicochemical drug properties with physiological and biochemical components. In our early investigations of poor drug absorption, several water-insoluble compounds and corresponding lysinate, succinate and phosphate esters were selected for comparison and studied in an in vitro rat intestinal ring system. The esters are relatively stable in solution and met the structural requirements for hydrolysis by enzymes of the intestinal brush border membrane. These conditions served the hypothesis that the more water-soluble derivatives would provide a higher concentration gradient from solution to the intestinal wall, thus increasing the driving force for absorption and hydrolysis to the pharmacologically active parent drug at the intestinal wall; in addition, the more lipophilic parent drug would be favored for partitioning into the membrane. It was found that uptake of hexadecyl lysinate was four orders-of-magnitude greater than hexadecanol because of its higher aqueous solubility. Further studies with hydrocortisone, its phosphate and succinate esters demonstrated that when the derivatives were incubated with tissue from the jejunum, hydrolysis to the parent compound occurred prior to absorption. Studies comparing the reconversion and uptake of prednisolone prodrugs by intestinal rings prepared from rat jejunum and colon revealed marked differences. Both phosphate and succinate steroid esters were absorbed well in the jejunum in the form of the parent compound. Only the succinate ester was taken up well by the colon, however, and was taken up by the tissue as the intact ester. The phosphate ester was neither hydrolyzed nor appreciably absorbed in the colon. Histochemical techniques and light microscopy confirmed high alkaline phosphatase reactivity toward hydrocortisone- and prednisolone-21-phosphate in the jejunum and an absence of activity in the colon. These results suggest a direct role for intestinal enzyme distributions in the design of site-targeted drug delivery.