Intestinal metabolism and transport of 5-aminosalicylate

The purpose of this study was to determine the characteristics of intestina l absorption and metabolism of B-aminosalicylic acid (5ASA). Regional perfu sions of 5ASA in the anesthetized rat resulted in the appearance of N-acety l-5-aminosalicylic acid in the intestinal lumen. Lumenal metabolite appeara nce was proportional to 5ASA permeability, which was 5-fold higher in the j ejunum than in the ileum. Intestinal elimination significantly decreases 5A SA absorption at low lumenal drug concentrations and this process is satura ted at high drug concentrations. Metabolite levels in intestinal tissue wer e higher than plasma levels at low perfusion drug concentrations, whereas t he reverse was observed at high concentrations. Transport and metabolism of 5ASA was studied in Caco-2 monolayers. At low drug concentrations, 5ASA wa s preferentially transported in the basolateral (BL) to apical (AP) directi on. With 5ASA incubation in either the AP or BL chamber, the N-acetyl metab olite appeared only in the AP compartment. Transport of N-acetyl-5-aminosal icylic acid was also exclusively observed in the BL to AP direction. Clinic al data indicate that anti-inflammatory response to oral 5ASA correlates wi th the amount of BASA delivered to the intestinal tissue. This study shows that at lumenal levels below 200 mu g/ml (concentrations that are typically achieved by controlled release dosage forms), intestinal secretion of 5ASA accounts for more than 50% of the total elimination and can significantly affect tissue levels and, therefore, may be an important factor in determin ing the response to 5ASA therapy.