A Colon-Specific Drug-Delivery System Based on Drug Glycosides and the Glycosidases of Colonic Bacteria

Article abstract of DOI:10.1021/jm00369a005

Steroid glycosides and the unique glycosidase activity of the colonic microflora form the basis of a new-colon-specific drug-delivery system.Drug glycosides are hydrophilic and, thus, poorly absorbed from the small intestine.Once such a glycoside reaches the colon it can be cleaved by bacterial glycosidases, releasing the free drug to be absorbed by the colonic mucosa.This concept was illustrated with dexamethasone 21-β-D-glucoside (1) and prednisolone 21-β-D-glucoside (2), two prodrugs that may be useful in treating inflammatory bowel disease.Hydrolysis of theprodrugs by β-glucosidase and fecal homogenates in vitro released the free steroids.Glucosides 1 and 2 were administered to rats intragastrically to determine when when and where the free steroids were released.Unmodified dexamethasone (3) and prednisolone (4) were also given to rats intragastrically to compare absorption of the glucosides with the free steroids.Both glucosides were found to reach the rat lower intestine in 4-5 h, where they were rapidly hydrolyzed, releasing the free steroids.Delivery of steroid 3 (via glucoside 1) was more specific than that of steroid 4 (via glucoside 2): nearly 60percent of an oral dose of glucoside 1 reached the cecum, whereas less than 15percent of glucoside 2 reached the cecum.When free steroids 3 and 4 were administered orally, they were almost exclusively absorbed in the small intestine: less than 1percent of an oral dose of each reached the cecum.