MOLECULAR CHARACTERIZATION OF INTESTINAL- ABSORPTION OF DRUGS BY CARRIER-MEDIATED TRANSPORT MECHANISMS

It has long been thought that intestinal absorption of most of the dru gs proceeds by passive diffusion mechanism, in which lipid solubility of the drug molecule is a determinant factor. However, water-soluble n atural compounds such as amino acids and sugars can move across cell m embranes by the specialized carrier-mediated transport mechanisms. Alt hough some drugs which are structurally analogous to natural compounds have been suggested to be absorbed by such transporters, no clear evi dence for the involvement of carrier-mediated transport mechanisms has been obtained. In the present study, through the approachs by means o f the molecular cloning and functional expression of drug transporters as well as membrane physiological analysis for the drug transport acr oss the intestinal epithelial cell membranes, participation of the car rier-mediated transport mechanisms for the drug absorption was clarifi ed. They include peptide transporter, monocarboxylic acid transporter, anion antiporter, and P-glycoprotein. Most of them have a function fo r the uptake of drugs into epithelial cells, leading to the increased absorption of drugs, whereas P-glycoprotein excludes drugs into the lu men, thereby decreasing the apparent absorbability of drugs. A rat int estinal monocarboxylic acid-proton cotransporter, MCT1, and an anion a ntiporter, AE2, were suggested to contribute to the pH-dependent intes tinal absorption of monocarboxylic acids such as benzoic acid, lactic acid, nicotinic acid, and valproic acid. An involvement of such pH-dep endent transporters in the intestinal absorption of weak organic acids is important, because they may have an alternative mechanism against passive diffusion according to the pH-partition hypothesis. PepT1 clon ed from rat intestinal epithelial cells as a peptide transporter was c larified to localize at the intestinal epithelial brush-border membran e and to function for the absorption of beta-lactam antibiotics by the proton-gradient energized mechanism. In contrast, P-glycoprotein func tions for the secretion of drugs into the intestinal lumen, thereby de creasing intestinal absorption of an immunosuppressive, cyclosporin A and a 5-HT3 receptor antagonist, azasetron.These lines of studies on t he clarification of carrier-mediated drug absorption mechanisms will p rovide new knowledge for the strategies to the enhancement of intestin al absorption of drugs.