title: Amino acid derivatives of 5-ASA as novel prodrugs for intestinal drug delivery.
abstract: 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, and N-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 and 2) 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 its N-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.
authors.affiliation: Clinica di Gastroenterologia ed Endoscopia Digestiva, Università degli Studi di Perugia, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Clerici
authors.forename: G
authors.initials: G
authors.lastname: Gentili
authors.forename: E
authors.initials: E
authors.lastname: Boschetti
authors.forename: C
authors.initials: C
authors.lastname: Santucci
authors.forename: A G
authors.initials: AG
authors.lastname: Aburbeh
authors.forename: B
authors.initials: B
authors.lastname: Natalini
authors.forename: R
authors.initials: R
authors.lastname: Pellicciari
authors.forename: A
authors.initials: A
authors.lastname: Morelli
mesh_terms: D000626:Aminopeptidases / Q000378:metabolism; D000636:Aminosalicylic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D002268:Carboxypeptidases / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003125:Colostomy; D043384:Glutamyl Aminopeptidase; D007408:Intestinal Absorption; D008297:Male; D019804:Mesalamine; D008871:Microvilli / Q000201:enzymology; D011355:Prodrugs / Q000627:therapeutic use*; D051381:Rats; D011919:Rats, Inbred Strains; D012460:Sulfasalazine / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000636:Aminosalicylic Acids; D011355:Prodrugs; D012460:Sulfasalazine; D019804:Mesalamine; D002268:Carboxypeptidases; D000626:Aminopeptidases; D043384:Glutamyl Aminopeptidase