Improving intestinal absorption of water-insoluble compounds: a membrane metabolism strategy

A strategy for improving the intestinal absorption of water-insoluble drugs was developed and tested. The strategy is based on making a soluble derivative of an insoluble compound which, in turn, is a substrate for enzymes in the surface coat of the brush border region of the microvillous membrane. Consequently, just prior to reaching the membrane, the physical properties of the diffusing species are changed from polar to nonpolar. The experimental test used two drug-drug derivative pairs, estrone-lysine estrone ester and p-nitroaniline-lysine p-nitroanilide. Wall permeabilities were determined using an external perfusion technique in the rat intestine and a laminar flow convective diffusion model for transport in the lumen. Analysis of the permeability results indicates that the derivatives have higher wall permeabilities than the parent compounds and that the microvillous surface coat may be a significant contributor to the intestinal wall resistance. Comparison of the absorption rates for estrone and the lysine estrone ester indicates that the absorption rate of the derivatives could be up to five orders of magnitude greater than that for the parent compound.