title: Gene ablation of carnitine/organic cation transporter 1 reduces gastrointestinal absorption of 5-aminosalicylate in mice.
abstract: 5-Aminosalicylic acid (5-ASA) is an orally administered therapeutic agent for inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease. We hypothesized that the absorption of 5-ASA is mediated by the polyspecific carnitine/organic cation transporter (OCTN1/SLC22A4), based on the similarity of chemical structure between 5-ASA and other OCTN1 substrates. Therefore, we examined the involvement of this transporter in the disposition of 5-ASA in vivo by using octn1 gene knockout (octn1(-/-)) mice. After oral administration of 5-ASA, the plasma concentrations of 5-ASA and its primary metabolite, N-acetyl-5-aminosalicylate (Ac-5-ASA), in octn1(-/-) mice were much lower than those in wild-type mice. The time required to reach maximum plasma concentration was also delayed in octn1(-/-) mice. On the other hand, the plasma concentration profiles of both 5-ASA and Ac-5-ASA after intravenous administration of 5-ASA (bolus or infusion) were similar in the two strains. Uptake of 5-ASA from the apical to the basal side of isolated small-intestinal tissues of octn1(-/-) mice, determined in an Ussing-type chamber, was lower than that in wild-type mice. Further, uptake of 5-ASA in HEK293 cells stably transfected with the OCTN1 gene, assessed as the sum of cell-associated 5-ASA and Ac-5-ASA, was higher than that in HEK293 cells transfected with the vector alone. Overall, these results indicate that OCTN1 is involved, at least in part, in the gastrointestinal absorption of 5-ASA.
authors.affiliation: Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University.
authors.forename: Takuya
authors.initials: T
authors.lastname: Shimizu
authors.forename: Ai
authors.initials: A
authors.lastname: Kijima
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Masuo
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ishimoto
authors.forename: Tomoko
authors.initials: T
authors.lastname: Sugiura
authors.forename: Saki
authors.initials: S
authors.lastname: Takahashi
authors.forename: Noritaka
authors.initials: N
authors.lastname: Nakamichi
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kato
mesh_terms: D000818:Animals; D001682:Biological Availability; D001693:Biological Transport, Active; D002331:Carnitine / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy*; D007408:Intestinal Absorption; D007421:Intestine, Small / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins; D019804:Mesalamine / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051379:Mice; D018345:Mice, Knockout; D027702:Organic Cation Transporter 1 / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion; D014162:Transfection
chemical_list: D008565:Membrane Proteins; D027702:Organic Cation Transporter 1; D019804:Mesalamine; D002331:Carnitine