C. Clerici et al., AMINO-ACID DERIVATIVES OF 5-ASA AS NOVEL PRODRUGS FOR INTESTINAL DRUG-DELIVERY, Digestive diseases and sciences, 39(12), 1994, pp. 2601-2606
In an attempt to obtain site-specific delivery of 5-ASA in the intesti
nal 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-amin
osalicyl-L-proline-L-leucine (3), and 5-(N-L-glutamyl)-aminosalicyl-L-
proline-L-leucine (4), which are selectively cleaved by intestinal bru
sh 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 metabol
ites, 5-ASA, and N-acetyl-5-ASA were measured by highperformance liqui
d chromatography. The absorption and metabolism of all compounds were
essentially identical in colostomized and normal animals. 5-ASA exhibi
ted a rapid proximal intestinal absorption as evidenced by the high cu
mulative urinary excretion (>65%) and low fecal excretion. Sulfasalazi
ne, as expected, exhibited a lower urinary recovery (<35%) and higher
fecal excretion of 5-ASA and its metabolite. The novel glutamate and a
spartate derivatives (1 and 2) behaved similarly to sulfasalazine, whi
le administration of the proline-leucine derivative (3) resulted in ur
inary and fecal recovery values intermediate with respect to those obs
erved with 5-ASA and sulfasalazine. 5-(NL-Glutamyl)-aminosalicyl-L-pro
line-L-leucine yielded the highest fecal recovery of 5-ASA and its N-a
cetyl derivative, indicating a more efficient delivery to the distal b
owel. 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.