Depending upon the sugar (monosaccharide) present in the drug-buffer solution (isotonic Krebs bicarbonate, pH 7.4), one can effectively alter the passive transfer of several drugs across the everted rat intestine. A similar phenomenon was noted in a previous study concerned with the influence of various cations on transfer. Thus, the transfer of riboflavin, salicylate, and sulfanilamide is significantly decreased in the presence of glucose. Concentrations of glucose as low as 25 mM were found to inhibit riboflavin transfer significantly. Phlorizin (1 mM), which is known to inhibit active glucose transport, abolishes the glucose-stimulated inhibition of riboflavin transfer. A similar inhibition of riboflavin transfer was noted in the presence of xylose. Mannitol, on the other hand, a nonpenetrating sugar, had no effect on the cumulative transfer of these compounds over a 2-hr. period. As noted in the previous study, there appears to be a good correlation between the extent of tissue-fluid uptake under various experimental conditions and the inhibition of riboflavin transfer. Thus, materials causing tissue-fluid uptake (e.g., glucose and xylose) inhibit riboflavin transfer; materials causing no tissue-fluid uptake (mannitol and glucose plus phlorizin) have no effect on drug transfer. Several plausible mechanisms are suggested to account for the observed decrease in passive drug transfer.