Glucose effects on intestinal drug absorption: Contributions of microclimatepH and paracellular pathway.

Abstract

Glucose influences on rat intestinal absorption of small peptide and weak base drugs have been studied as a function of molecular size and ionization. Absorption was assessed from perfusions in situ and in Ussing chambers and everted rings in vitro. The roles of variable microclimate pH and paracellular transport were examined by comparing the effects of actively-transported monosaccharides with mannitol at varying luminal pH. D-glucose stimulation of intestinal water absorption enhanced the absorption of selected di- and tripeptides but did not increase the permeability of the larger hexa- and octapeptides. The increased uptake of the smaller peptides is a function of enhanced paracellular transport by solvent drag and transcellular transport by augmented proton gradient. D-glucose did not increase the jejunal permeability of cimetidine (M.W. 252, pKa 7.1) from in situ perfusion at pH 5.5, 6.5 or 7.5 in spite of consistent stimulation of net water absorption. In contrast, the permeability of aminomethylpyridine (M.W. 108, pKa 7.2) was increased by D-glucose at all of the pHs tested, consistent with an increase in net water absorption. The nonmetabolizable sugar, 3-o-methylglucose, enhanced cimetidine permeability only at a luminal pH of 7.5, while this sugar enhanced aminomethylpyridine permeability at each of the luminal pHs tested. This finding is consistent with solvent drag of the smaller solute through paracellular pathways independent of the fraction of ionized drug in the mucosal microclimate. Since the nonmetabolizable sugar generates solvent drag without altering microclimate pH, these results suggest that the paracellular pathway excludes cationic cimetidine to a greater extent than the uncharged base. It is also likely that possible cimetidine GI pharmacological activity (e.g., inhibition on the mucosal sodium/proton exchange) may contribute to the apparent restriction of the paracellular pathway to cationic cimetidine. In Ussing chamber studies, high mucosal concentrations of D-glucose were shown to reduce transepithelial jejunal resistance while 3-o-methylglucose failed to alter baseline conductivity. Streaming potential studies showed that glucose did not alter aqueous resistance in this in vitro system. The above results are consistent with a glucose-metabolism effect on paracellular expansion responsible for absorption enhancement of low molecular weight drugs and contributing to variable absorption of ionized drugs.