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.


CONCLUSIONS
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).
Xin
Hua-Wen
HW
Department of Clinical Pharmacology, Wuhan General Hospital, Wuhan, People's Republic of China.
Schwab
Matthias
M
Klotz
Ulrich
U
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000187:drug effects; D004077:Digoxin / Q000378:metabolism / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007444:Inulin / Q000378:metabolism / Q000493:pharmacokinetics; D018374:LLC-PK1 Cells; D026901:Membrane Transport Proteins / Q000235:genetics / Q000502:physiology*; D019804:Mesalamine / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000502:physiology*; D013552:Swine; D014162:Transfection; D014316:Tritium
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004077:Digoxin; D007444:Inulin; D026901:Membrane Transport Proteins; D019804:Mesalamine; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D014316:Tritium; C000715087:ABCC2 protein, human