Transport studies with 5-aminosalicylate.
OBJECTIVE: It is generally accepted that 5-aminosalicylate (5-ASA; mesalamine), widely used in inflammatory bowel disease therapy, exerts its action from the intraluminal site of the intestine. In addition to local metabolism of 5-ASA, it has been assumed that therapeutic mucosal concentrations of 5-ASA depend on transporter-mediated secretion back to the lumen. METHODS: We tested the hypothesis that 5-ASA represents a substrate of P-glycoprotein (P-gp) and/or multidrug resistance-associated protein 2 (MRP2), thereby possibly contributing to variable therapeutic effects. Polarized, basal-to-apical transport of [(3)H]5-ASA was studied in monolayers of Caco-2 and L-MDR cells, both of which express P-gp in their apical membrane, as well as in MDCK cells transfected with human MRP2. Moreover, we investigated the influence of 5-ASA on transport of digoxin in Caco-2 cells. RESULTS: In Caco-2 cells a P-gp-mediated efflux of 5-ASA (5-500 muM) could be excluded. Likewise, in L-MDR1 and MRP2 cells no transport differences in either the basal-to-apical or apical-to-basal direction were measurable. 5-ASA (50 muM to 5 mM) had no effect on the transport of digoxin. CONCLUSION: From these in-vitro experiments one can conclude that intestinal secretion of 5-ASA is apparently not mediated by P-gp or MRP2. Further studies are needed to identify the nature of the involved active carrier system(s).