Premium
Glucocorticoid‐dextran conjugates as potential prodrugs for colonspecific delivery: Steady‐state pharmacokinetics in the rat
Author(s) -
McLeod Andrew D.,
Tolentino Lorna,
Tozer Thomas N.
Publication year - 1994
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.2510150207
Subject(s) - dexamethasone , dextran , pharmacokinetics , prodrug , pharmacology , glucocorticoid , chemistry , corticosteroid , medicine , colitis , endocrinology , biochemistry
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.