title: Glucocorticoid-dextran conjugates as potential prodrugs for colon-specific delivery: hydrolysis in rat gastrointestinal tract contents.
abstract: Chronic colitis, e.g., ulcerative colitis and Crohn's disease, is presently treated with glucocorticoids and other antiinflammatory agents. Side effects limit chronic glucocorticoid therapy. The dose, and consequently the side effects, may be reduced by using prodrugs that selectively deliver drug to the colon. We previously synthesized glucocorticoid-dextran conjugates in which dexamethasone and methylprednisolone were attached to dextran (weight-average molecular weight = 72,600) using dicarboxylic acid linkers (succinate and glutarate). In the present study, the hydrolysis kinetics of the hemiesters (hemiester = glucocorticoid+linker) and dextran conjugates were determined after incubation at 37 degrees C in diluted luminal contents of the gastrointestinal (GI) trace of male Sprague-Dawley rats. The hemiesters were rapidly hydrolyzed in the proximal small intestine (e.g., dexamethasone-hemiglutarate t1/2 = 0.5 h). This rate decreased progressively down the GI tract (t1/2 = 4.8, 54, and 68 h in distal small intestine, cecum, and colon, respectively). The enzyme responsible for hemiester hydrolysis, apparently a type-A alkaline carboxylesterase, is probably of host origin because its activity is highest in the small intestine where bacterial count is low. The dextran conjugates resisted hydrolysis in upper GI tract contents but were rapidly degraded in cecal and colonic contents where the bacterial count is high. The dextran conjugate tested, methylprednisolone-succinate-dextran, was easily hydrolyzed by an endodextranase, indicating that substrate specificity is not lost upon the attachment of glucocorticoid. The results of this study indicate that dextran conjugates may be useful in selectively delivering glucocorticoids to the large intestine for the treatment of colitis.
authors.affiliation: Department of Pharmacy, School of Pharmacy, University of California, San Francisco 94143-0446.
authors.forename: A D
authors.initials: AD
authors.lastname: McLeod
authors.forename: D R
authors.initials: DR
authors.lastname: Friend
authors.forename: T N
authors.initials: TN
authors.lastname: Tozer
mesh_terms: D000693:Anaerobiosis; D000818:Animals; D002850:Chromatography, Gel; D003106:Colon / Q000378:metabolism*; D003911:Dextrans / Q000737:chemistry*; D004064:Digestive System / Q000378:metabolism*; D016503:Drug Delivery Systems; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005938:Glucocorticoids / Q000008:administration & dosage / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D008297:Male; D011355:Prodrugs / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D003911:Dextrans; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D011355:Prodrugs