N-Succinylaspart-1-yl Celecoxib is a Potential Colon-Specific Prodrug of Celecoxib with Improved Therapeutic Properties

To develop a colon-specific prodrug of celecoxib, a cyclooxygenase-2 selective inhibitor, which could improve cardiovascular toxicity and therapeutic effectiveness for chemoprevention of colorectal cancer, aspart-1-yl celecoxib (A1C) or aspart-4-yl celecoxib (A4C), succinyl celecoxib (SC), and N-succinylaspart-1-yl celecoxib (SA1C) or N-succinylaspart-4-yl celecoxib (SA4C) were prepared and evaluated as a prodrug with such beneficial properties. On incubation with the small intestinal contents while SC, SA1C, and SA4C were stable, A1C and A4C were degraded to liberate celecoxib. In the cecal contents, the other conjugates except for SC and SA4C were cleaved to release celecoxib. These results suggest the colon-specific delivery and activation of SA1C. On oral administration of SA1C or celecoxib, no SA1C was detected in the blood and urine, indicating the limited absorption of SA1C. SA1C delivered a much greater amount of celecoxib to the large intestine while keeping the plasma concentration of celecoxib at much lower level, which is consistent with no change of the serum level of 6-ketoprostaglandin F1α whose decrease is associated with the cardiovascular toxicity of celecoxib. Moreover, SA1C administered orally supplied a greater concentration of celecoxib for the whole colonic tissue. Taken together, SA1C may be a colon-specific prodrug of celecoxib with improved therapeutic properties. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:1831–1842, 2012