The long-term objective of the proposed research is to develop new, clinically useful, therapeutic treatments for diseases of the large intestine, such as inflammatory bowel disease (IBD). The approach is based on delivery of antiinflammatory (or other) agents via a prodrug carrier to the large intestine. The active drug is liberated by enzymes produced by gut microflora, which reside primarily in the large intestine. Once released, the drug is absorbed, leading to higher cecal and colon tissue levels than are possible when the same agent is administered systemically at an equal molar dose.
The specific aims of the proposed work are to (1)synthesize the beta-D-glucuronides of dexamethasone and flunisolide, (2) study the hydrolysis of the prodrugs under in vitro conditions in rat (normal, germfree, and rats with colitis) intestinal contents and tissues and in human fecal samples from normal and IBD patients, (3) study drug delivery in normal and germfree rats at or near pharmacologically relevant doses. (4) conduct efficacy studies [assessment of gross morphologic injury, histologic injury, in vivo fluid and electrolyte absorption, in vitro solute transmural flux measurements, myeloperoxidase activity, and eicosanoid (PGE2 and LTB4) levels in the colonic lumen] in colitis-induced rats (normal and germfree) and relate the results with those obtained in specific aims 2 and 3, and (5) measure serum ACTH levels in both prodrug and drug treated animal in specific aim 4.
Specific aim 1 is designed to provide sufficient prodrug for testing in vitro and in vivo.
Specific aims 2 and 3 are designed to determine the role of bacterial and mammalian enzymes in colon specificity, as well as the ability of the prodrug to limit absorption of the drug in the GIT.
Specific aim 4 is designed to establish the relationship between the pharmacokinetics of drug delivery and the efficacy observed in guinea pigs.
Specific aim 5 is designed to assess the potential of the delivery system to reduce side effects commonly associated with chronic administration of corticosteroids. Current studies indicate that, using the prodrug dexamethasone beta-D- glucoside, a selective advantage in cecal and colon tissue levels over time is gained relative to the active agent delivered by intravenous administration. On the basis of results from pharmacokinetic and efficacy studies, the primary advantage of the proposed system is the ability to deliver therapeutically effective amounts of dexamethasone or flunisolide, via a glycoside prodrug, to the large intestinal mucosa using lower administered doses than required with systemic administration. This finding suggests that the side effects of corticosteroids could be markedly reduced relative to systemic administration. The development of a colon-specific delivery system will be useful to many people worldwide who suffer from IBD. Individuals with IBD are at a significantly greater risk of developing colon cancer. Delivering corticosteroids locally to the colon of patients following radiation therapy for treatment of uterine and prostate cancers would help alleviate the effects of radiation-induced colitis. Other potential applications include localized delivery of 5-fluorouracil (5-FU) for treatment of colon cancer, slow infusion of 5-FU into the hepatic portal system to help control secondary hepatic tumors and delivery of drugs to the lower intestine to help control spastic colon and irritable bowel syndrome using anticholinergics or antispasmotics.
