Amino acid derivatives of 5-ASA as novel prodrugs for intestinal drug delivery

In an attempt to obtain site-specific delivery of 5-ASA in the intestinal tract, we have determined the extent of absorption and metabolism of a number of novel 5-ASA derivatives, namely, (N-l-glutamyl)-amino-2-salicylic acid (1), (N-l-aspartyl)-amino-2-salicylic-acid (2), 5-aminosalicyl-l-proline-l-leucine (3), and 5-(N-l-glutamyl)-aminosalicyl-l-proline-l-leucine (4), which are selectively cleaved by intestinal brush border aminopeptidase A and carboxypeptidases. These novel prodrugs, 5-ASA, and sulfasalazine were administered to adult Fisher rats (N=30) and to animals that had undergone prior colostomy (N=30). Urine and feces were collected at timed intervals for 48 hr and the metabolites, 5-ASA, andN-acetyl-5-ASA were measured by high-performance liquid chromatography. The absorption and metabolism of all compounds were essentially identical in colostomized and normal animals. 5-ASA exhibited a rapid proximal intestinal absorption as evidenced by the high cumulative urinary excretion (>65%) and low fecal excretion. Sulfasalazine, as expected, exhibited a lower urinary recovery (<35%) and higher fecal excretion of 5-ASA and its metabolite. The novel glutamate and aspartate derivatives (1 and2) behaved similarly to sulfasalazine, while administration of the proline-leucine derivative (3) resulted in urinary and fecal recovery values intermediate with respect to those observed with 5-ASA and sulfasalazine. 5-(N-l-Glutamyl)-aminosalicyl-l-proline-l-leucine yielded the highest fecal recovery of 5-ASA and itsN-acetyl derivative, indicating a more efficient delivery to the distal bowel. Amino acid derivatives of 5-ASA appear to be potentially useful prodrugs for the site-specific delivery of 5-ASA to different regions of the intestinal tract.We acknowledge the Depha Team for financial support and Dr. Kenneth D.R. Setchell for discussions.