6-ketoprostaglandin-f1-alpha and Adenomatous-Polyposis-Coli

In general, colon-specific delivery of a drug decreases systemic absorption and increases therapeutic concentration of the drug at the target site. N-succinylglutam-1 or 5-yl celecoxib (SG1C and SG5C) were prepared as a colon-specific prodrug of celecoxib, a selective Cox-2 inhibitor, and investigated whether the celecoxib derivatives could deliver celecoxib to the target site and improve cardiovascular toxicity and therapeutic effectiveness for the treatment of familiar adenomatous polyposis. SG1C and SA5C were cleaved to release celecoxib in the cecal contents while stable in small intestinal contents. The cecal release of celecoxib was much greater for SG1C than SG5C. SG1C administered orally was barely detected in the blood and urine. SG1C delivered much greater amount of celecoxib to the large intestine while keeping the plasma concentration of celecoxib at much lower level compared with oral administration of free celecoxib. Consistent with these pharmacokinetic results, SG1C supplied a greater concentration of celecoxib for the entire colonic tissue and did not change the serum level of 6-keto-PGF(1α) whose decrease is associated with the cardiovascular toxicity of celecoxib. Taken together, colon-specific delivery of celecoxib using a prodrug approach may be a useful strategy to improve toxicological and pharmacological properties of celecoxib.

Topics: 6-Ketoprostaglandin F1 alpha; Adenomatous Polyposis Coli; Animals; Aspartic Acid; Cecum; Celecoxib; Chemistry Techniques, Synthetic; Chromatography, High Pressure Liquid; Colon; Cyclooxygenase 2 Inhibitors; Drug Delivery Systems; Drug Stability; Glutamates; Intestinal Absorption; Male; Molecular Structure; Prodrugs; Pyrazoles; Rats; Rats, Sprague-Dawley; Solubility; Sulfonamides; Tissue Distribution

Epidemiologic and animal studies indicate that sustained use of non-steroidal anti-inflammatory drugs (NSAIDs) have a chemopreventive effect against the incidence of colorectal neoplasia and subsequent mortality. We previously demonstrated that sulindac significantly reduces intestinal tumor load in Apc(Min/+)mice and the tumor regression was not necessarily correlated with prostaglandin biosynthesis. In the present study, we further investigate the relationship of NSAID treatment and tumorigenesis in the Apc(Min/+)mouse model. We demonstrate that indomethacin (9 ppm) is a very potent chemopreventive agent, reducing tumor load by 85% and significantly inhibiting basal and ex vivo prostaglandin formation (P< 0.006 and P< 0.0001, respectively). Aspirin (400 ppm) has a similar impact on reducing prostaglandin levels, but in contrast to indomethacin, is uneffective in reducing the tumor load. The data indicate a discordance between the impact of different NSAIDs on tumorigenesis in Apc(Min/+)mice.

Topics: 6-Ketoprostaglandin F1 alpha; Adenomatous Polyposis Coli; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Arachidonic Acid; Aspirin; Body Weight; Dinoprostone; Eating; Indomethacin; Intestinal Mucosa; Intestinal Neoplasms; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Prostaglandin Antagonists

Recent studies indicate that nonsteroidal anti-inflammatory drugs have a chemopreventive effect against colorectal neoplasia. Nonsteroidal anti-inflammatory drugs inhibit cyclooxygenases, principal enzymes that mediate the formation of prostanoids. To determine whether prostanoids are involved in the pathogenesis of colorectal adenomas, we compared the levels of five major stable metabolic products of the cyclooxygenase pathway in the normal-appearing mucosa and in adenomas of patients with familial adenomatosis polyposis. Of 12 patients tested, 6 had elevated levels of at least one prostanoid in the adenomas. More importantly, the relative levels of three prostanoids [prostaglandin (PG)D2, PGE2, and 6-keto-PGF1alpha] were elevated in adenomas compared to normal-appearing mucosa from the same patients, and the resulting ratios were correlated with the size of the adenoma. These results suggest a role for prostanoids in progression of colorectal polyposis in familial adenomatosis polyposis patients.

Topics: 6-Ketoprostaglandin F1 alpha; Adenoma; Adenomatous Polyposis Coli; Adult; Dinoprost; Dinoprostone; Female; Humans; Intestinal Mucosa; Male; Oxytocics; Prostaglandin D2; Prostaglandins; Thromboxane B2