title: Glucocorticoid-dextran conjugates as potential prodrugs for colon-specific delivery: steady-state pharmacokinetics in the rat.
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 was attached to dextran (weight-average molecular weight = 72,600) using dicarboxylic acid linkers (succinate and glutarate). In the present study, dexamethasone-succinate-dextran and dexamethasone-glutarate-dextran were administered to two groups of male Sprague-Dawley rats by intragastric infusion. In two additional groups, disodium dexamethasone phosphate and dexamethasone hemisuccinate were each administered by subcutaneous infusion. In a fifth group, dexamethasone was administered by intragastric infusion. All groups were infused for sufficient time for steady state to be achieved. Colon-specific delivery was quantified using a drug-delivery index (DDI) in which steady-state dexamethasone concentrations in the cecum and colon were compared with those measured in blood after separate administrations of dexamethasone and dexamethasone-dextran conjugate. The colonic DDI values for dexamethasone-succinate-dextran and dexamethasone-glutarate-dextran were approximately seven and four, respectively. These values were a result of higher tissue concentrations and lower blood concentrations of dexamethasone after intragastric administration of the conjugates compared to subcutaneous and intragastric administration of dexamethasone. The pharmacokinetics of methyl-prednisolone was also investigated after subcutaneous infusion. Observed cecal and colonic tissue-to-blood ratios of 19:1 and 12:1, respectively, showed that this drug is extensively delivered to the large intestine even after subcutaneous administration.
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: L
authors.initials: L
authors.lastname: Tolentino
authors.forename: T N
authors.initials: TN
authors.lastname: Tozer
mesh_terms: D000818:Animals; D003106:Colon / Q000378:metabolism*; D003907:Dexamethasone / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000493:pharmacokinetics; D003911:Dextrans / Q000378:metabolism* / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D008297:Male; D008775:Methylprednisolone / Q000378:metabolism* / Q000493:pharmacokinetics; D008962:Models, Theoretical; D011355:Prodrugs / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D003911:Dextrans; D011355:Prodrugs; D003907:Dexamethasone; D008775:Methylprednisolone