Steady-state pharmacokinetics of corticosteroid delivery from glucuronide prodrugs in normal and colitic rats

• Published in: Biopharmaceutics & drug disposition 1997-11, Vol.18 (8), p.681-695
• Main Authors: Nolen III, Harold W., Fedorak, Richard N., Friend, David R.
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents - administration & dosage; Anti-Inflammatory Agents - pharmacokinetics; Biological and medical sciences; Biological Availability; budesonide; Budesonide - administration & dosage; Budesonide - pharmacokinetics; Colitis, Ulcerative - blood; Colitis, Ulcerative - metabolism; Colon - metabolism; colonic delivery; dexamethasone; Dexamethasone - administration & dosage; Dexamethasone - pharmacokinetics; Digestive system; Disease Models, Animal; Drug Delivery Systems; Glucocorticoids - administration & dosage; Glucocorticoids - pharmacokinetics; Glucuronates - administration & dosage; Glucuronates - pharmacokinetics; glucuronide; Injections, Subcutaneous; Male; Medical sciences; Pharmacology. Drug treatments; prodrug; Prodrugs - administration & dosage; Prodrugs - pharmacokinetics; Rats; Rats, Sprague-Dawley; ulcerative colitis
• ISSN: 0142-2782; 1099-081X
• DOI: 10.1002/(SICI)1099-081X(199711)18:8<681::AID-BDD56>3.0.CO;2-A

Ulcerative colitis and Crohn's colitis are chronic intestinal diseases usually treated with various nonsteroidal antiinflammatory agents to maintain remission. Corticosteroids, while useful in acute treatment of these diseases, present side‐effects generally too serious to allow maintenance therapy. Colon‐specific drug delivery may permit use of corticosteroids for maintenance therapy if doses can be reduced while maintaining efficacy. In this study, two prodrugs (dexamethasone‐β‐D‐glucuronide (DXglrd) and budesonide‐β‐D‐glucuronide (BUDglrd)) were administered by intragastric (ig) infusion to conventional and colitic rats. In addition, dexamethasone (DX) and budesonide (BUD) were administered either ig or subcutaneously (sc) to healthy and colitic rats. Colon‐specific delivery was assessed using the drug delivery index (DDI). In conventional rats, DDIs for DXglrd ranged from about five to as high as 11 in the luminal contents relative to DX administered sc or ig. DDI values were also elevated in the mucosa of both healthy and colitic rats following ig administration of DXglrd. BUD was delivered somewhat less effectively from BUDglrd to the rat large intestine than was DX from DXglrd. The data are consistent with efficacy studies and support the conclusion that local delivery of corticosteroids to the large intestine is due, at least in part, to higher levels of drug delivery into the mucosal tissues. ©1997 John Wiley & Sons, Ltd.