Preparation and in vitro evaluation of celecoxib-amino acid conjugates as a colon specific prodrug

To develop a colon specific prodrug of celecoxib with improved therapeutic potency and cardiovascular toxicity for chemoprevention of colorectal adenomas, we prepared glycyl celecoxib (GC), aspart-1-ylcelecoxib (A1C) and glutam-1-ylcelecoxib (G1C) and examined colon specific properties in vitro. The amino acid conjugation lowered the apparent partition coefficient of celecoxib (4.6) to 1.2 (GC), 0.6 (A1C) and 0.8 (G1C). The celecoxib-amino acid conjugates were stable in pH 1.2 and 6.8 buffer solutions. On incubation with the contents of small intestine, while GC was stable up to 10 h, A1C and G1C were degraded and liberated celecoxib up to 19-32 % of the dose at 10 h. In the cecal contents, the three conjugates were cleaved to release celecoxib and amounts of celecoxib released from GC, A1C and G1C were 20, 64 and 55 % at 10 h and 30, 75 and 60 % of the dose at 24 h, respectively. Taken together, while GC may deliver celecoxib to the large intestine without premature degradation in the upper intestine, A1C and G1C may have advantages over GC in that they are less absorbable in the upper intestine due to lower partition coefficient and are converted to celecoxib more efficiently at the target site.