Gene Ablation of Carnitine/Organic Cation Transporter 1 Reduces Gastrointestinal Absorption of 5-Aminosalicylate in Mice
| Autor: | Noritaka Nakamichi, Takuya Shimizu, Yusuke Masuo, Ai Kijima, Saki Takahashi, Tomoko Sugiura, Takahiro Ishimoto, Yukio Kato |
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| Rok vydání: | 2015 |
| Předmět: |
Male
gastrointestinal absorption Biological Availability Biological Transport Active Pharmaceutical Science Pharmacology Transfection Mice Bolus (medicine) In vivo Oral administration Carnitine 5-aminosalicylate Intestine Small medicine Animals Humans Mesalamine Gene knockout Sequence Deletion Mice Knockout Organic cation transport proteins biology Chemistry Organic Cation Transporter 1 Membrane Proteins Transporter General Medicine organic cation transporter Inflammatory Bowel Diseases digestive system diseases HEK293 Cells surgical procedures operative Intestinal Absorption Biochemistry biology.protein medicine.drug |
| Zdroj: | Biological & Pharmaceutical Bulletin. 38:774-780 |
| ISSN: | 1347-5215 0918-6158 |
| DOI: | 10.1248/bpb.b15-00109 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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