Gene Ablation of Carnitine/Organic Cation Transporter 1 Reduces Gastrointestinal Absorption of 5-Aminosalicylate in Mice
Open accessAbstract
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.
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SLC22A4 and its homologues have significant specificity for ERG and weak activity for various drugs.
“Subsequent work(87,169–172) has confirmed and reinforced this view of SLC22A4 and its homologues(173) as having significant specificity for ERG, and weak activity for various drugs(174–177).”
From The biology of ergothioneine, an antioxidant nutraceutical (2020) · cites this paper as [176]
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- Authors
- Shimizu, T., Kijima, A., Masuo, Y., Ishimoto, T., Sugiura, T., Takahashi, S., Nakamichi, N., & Kato, Y.
- Affiliations
- Kanazawa University (JP)
- ORCID
- Venue
- Biological & Pharmaceutical Bulletin
- Publisher
- Pharmaceutical Society of Japan
- Published
- 2015
- Volume
- 38
- Issue
- 5
- Pages
- 774-780
- ISSN
- 0918-6158 (ISSN-L)
- 1347-5215
- OpenAlex
- W2130610134
- Cited by
- 8
- References
- 33
- Citations by year
- 2026: 1 · 2024: 2 · 2021: 2 · 2020: 2 · 2018: 1
- FWCI
- 0.15
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Locations
- Biological and Pharmaceutical Bulletin (publishedVersion)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc-nd)
- Kanazawa University Repository for Academic Resources (DSpace) (Kanazawa University) (submittedVersion, cc-by-nc-nd)
- Funders
- Hoansha Foundation
- Kanazawa University
- Ministry of Education, Culture, Sports, Science and Technology
- National Institute of Biomedical Innovation
- Japan Society for the Promotion of Science (25460092, 15H04664, 15J03940)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
- Keywords
- 5-aminosalicylic acid, OCTN1, SLC22A4, knockout mice, gastrointestinal absorption, small intestine, oral bioavailability, inflammatory bowel disease, drug transporters
- MeSH terms
- Animals, Biological Availability, Biological Transport, Active, Carnitine, Humans, Intestinal Absorption, Intestine, Small, Male, Membrane Proteins, Transfection, Inflammatory Bowel Diseases, Sequence Deletion, Mice, Knockout, Mesalamine, Organic Cation Transporter 1, Mice, HEK293 Cells
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