Dexamethasone-beta-D-glucoside is a potential prodrug for colonic delivery of the antiinflammatory agent dexamethasone. To deliver dexamethasone selectively to the colon, the glycoside prodrug must be slowly absorbed from the alimentary canal and it must be chemically and enzymatically stable in the stomach and small intestine. Once the prodrug reaches the large intestine, it should be quantitatively hydrolyzed to release the active agent. The potential of dexamethasone-beta-D-glucoside for colon-specific delivery of dexamethasone was first assessed in the rat, and more recently in the guinea pig, an animal in which an inflammatory bowel disease (IBD) model had been developed. The hydrolytic activity of both the tissues and contents of the guinea pig stomach, proximal and distal portions of the small intestine, cecum, and colon were measured. For the tissues, beta-D-glucosidase activity was greatest in the proximal small intestine while the contents of the cecum and colon showed the greatest beta-D-glucosidase activity. The luminal contents retained their activity even after repeated centrifugation and resuspension in a buffer; the activity was also unaffected by homogenization. Movement and hydrolysis of dexamethasone-beta-D-glucoside down the gastrointestinal tract (GIT) in the guinea pig was also examined. About 20 to 30% of an oral dose appeared to reach the guinea pig cecum. Here the prodrug was rapidly hydrolyzed to the active drug. From intravenous administration of the prodrug and drug, it is apparent that dexamethasone-beta-D-glucoside is poorly absorbed in the GIT (bioavailability < 1%). There is a selective advantage for delivery of dexamethasone in cecal tissues of about 9 in the guinea pig under conditions of this experiment. In another study, degraded carrageenan was used to develop experimental IBD in the guinea pig. Following oral dosing of dexamethasone-beta-D-glucoside (1.3-mu-mol/kg or 0.65-mu-mol/kg), dexamethasone (1.3-mu-mol/kg), or the dosing vehicle (H2O/EtOH, 0.95:0.05, v/v), the total number of ulcers in each group of animals was counted. Relative to control animals (dosing vehicle only), the drug and prodrug treatments significantly (P < 0.05) reduced the total number of ulcers. While there was no difference statistically between the drug and prodrug treatments, the results indicate that a lower dose of dexamethasone, administered as its glucoside prodrug, can be equally efficacious relative to higher dose of dexamethasone. This conclusion is consistent with the pharmacokinetic data obtained in normal guinea pigs and suggests there is a potential to decrease the usual dose of corticosteroids with a concomitant reduction in the systemic exposure.
