Regulation Mechanisms of Drug Disposition via H^+-Coupled Active Transport Systems in the Intestinal and Renal Tubular Epithelial Cells

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The absorptive and the secretory processes play important roles for the regulation of drug disposition in the body. Using the isolated plasma membrane vesicles, we have demonstrated H^+/organic cation antiport system (secretion) in renal brush border membranes and H^+/amino-beta-lactam antibiotic (dipeptide) cotransport system (absorption) in the intestinal brush border membranes. In the present study, we examined the structure and the regulatory mechanisms for H^+ coupled transport systems.1. The H^+/organic cation antiport system in renal brush border membranes is very sensitive to pH (optimum pH of 7.0), in contrast to organic anion and D-glucose transport systems, and that pH is an important factor to regulate the activity of the H^+/organic cation antiport system, as well as H^+ gradient (a driving force).2. Aminocephalosporins, such as cephradine, possessing an alpha-amino group and a carboxyl group, were transported via H^+/dipeptide cotransport system in the intestinal brush border membranes. Cefixime, a new p.o. cephalosporin with two carboxyl groups, was transported by an inward H^+ gradient via dipeptide carrier only in an acidic pH region, whereas cephradine is transported via dipeptide carrier in both neutral and acidic pH regions, suggesting the existence of multiple transport systems for dipeptides.3. Using the chemical modification technique to the membranes, we examined the role of sulfhydryl, histidine, tyrosine and carboxyl groups on the H^+/organic cation antiport system and H^+/dipeptide cotransport system. Histidine group was essential for both transport systems, and sulfhydryl group was essential for the H^+/organic cation antiport system.