COMPARATIVE-STUDY OF ACTIVE ABSORPTION BY THE INTESTINE AND DISPOSITION OF ANOMERS OF SUGAR-CONJUGATED COMPOUNDS

Active absorption in the intestine and metabolism of the beta- and alpha-anomers of the glucoside and galactoside of p-nitrophenol (p-NP) were studied to find a more suitable prodrug for poorly absorbed drugs. The everted sac technique was used to investigate the intestinal absorption of these glycosides at 250 muM from the mucosal to the serosal side in the rat jejunum. The absorption clearance of p-nitrophenyl alpha-D-glucopyranoside (p-NPalphaglc) (0.271 +/- 0.089 muL/min/cm, mean +/- SE, N = 8) was much lower than that of p-nitrophenyl beta-D-glucopyranoside (p-NPbetaglc) (4.45 +/- 0.34 muL/min/cm, mean +/- SE, N = 4) which is actively absorbed by a glucose transport carrier [Mizuma et al., Biochem Pharmacol 43: 2037-2039, 1992]. However, the major constituent appearing on the serosal side was p-NP (aglycone) after absorption of pNPalphaglc, whereas it was p-NPbetaglc itself after absorption of p-NPbetaglc The total amount transported to the serosal side after 20 min of p-NPalphaglc absorption, which was similar to that of p-NPbetaglc, was significantly decreased in the absence of Na+, indicating the active absorption of p-NPalphaglc by a Na+-dependent glucose transport carrier. Perfusion with a mucosal solution of p-NPalphaglc showed that the p-NP concentration on the serosal side (15.8 +/- 1.56 muM, mean +/- SE, N = 3) was significantly (P < 0.05) higher than that on the mucosal side (5.84 +/- 1.24 muM, mean +/- SE, N = 3) at 20 min. This indicated that the p-NP appearing on the serosal side was derived not from absorption of p-NP but from hydrolysis of p-NPalphaglc through the intestinal membrane during absorption. On the other hand, after absorption of p-nitrophenyl beta-D-galactopyranoside (p-NPbetagal), which is actively absorbed by glucose transport carrier, p-NPbetagal itself appeared mostly on the serosal side. However, p-nitrophenyl alpha-D-galactopyranoside (p-NPalphagal) absorption, which resulted in appearance on the serosal side, was not significantly decreased in the presence of 1 mM phloridzin or in the absence of Na+, indicating that the contribution of the glucose transport carrier to p-NPalphagal absorption was minimal. The order of the Na+-dependent intestinal absorption was p-NPbetaglc > p-NPalphaglc > p-NPbetagal > p-NPalphagal.