Drug glycosides: potential prodrugs for colon-specific drug delivery

摘要: The influence of prodrug structure on specificity glycoside/glycosidase based colon-specific drug delivery was studied by preparing nine steroid glycosides, measuring their relative lipophilicities, and hydrolyzing them with bacterial glycosidases from rat intestines. 21-yl beta-D-glucosides galactosides dexamethasone, prednisolone, hydrocortisone, fludrocortisone the beta-D-cellobioside prednisolone were prepared a modified Koenigs-Knorr reaction. deacetylated glycoside prodrugs, along P-nitrophenyl derivatives beta-D-glucoside, galactoside, cellobioside, subjected to hydrolysis contents stomach, proximal small intestine (PSI), distal (DSI), cecum. All prodrugs hydrolyzed slowly PSI stomach contents, more rapidly DSI, most cecal contents. This is basis site-specific reported earlier (Friend, D. R.; Chang, G. W. J. Med. Chem. 1984, 27, 261). Furthermore, themselves had very different susceptibilities hydrolysis. Hydrolysis rates catalyzed DSI decreased in following order: prednisolon-21-yl beta-D-galactoside (10) greater than beta-D-glucoside (2) (13) dexamethason-21-yl (9) (1). cellobioside 13 only half that glucoside 2 one-fourth galactoside 10. all rapid, exceptions hydrocortison-21-yl (5) fludrocortison-21-yl (7), which other prodrugs. Eadie-Hofstee plots for compounds suggested beta-D-glucosidase activity colon may be heterogeneous nature beta-D-galactosidase activity. Relative lipophilicities free steroids compared octanol-buffer partition coefficients (P). logarithm P (-0.56) considerably lower ranged 0.11 0.84. Log 1.54 1.73. These previously animal experiments, enable one estimate site prior extensive studies.