Gene Ablation of Carnitine/Organic Cation Transporter 1 Reduces Gastrointestinal Absorption of 5-Aminosalicylate in Mice

フォーマット:

論文

責任表示:

Shimizu, Takuya ; Kijima, Ai ; Masuo, Yusuke ; Ishimoto, Takahiro ; Sugiura, Tomoko ; Takahashi, Saki ; Nakamichi, Noritaka ; Kato, Yukio

言語:

英語

出版情報:

日本薬学会 = The Pharmaceutical Society of Japan, 2015-01-01

著者名:

Shimizu, Takuya

Kijima, Ai

Masuo, Yusuke

Ishimoto, Takahiro

Sugiura, Tomoko

Takahashi, Saki

Nakamichi, Noritaka

Kato, Yukio

続きを見る

掲載情報:

Biological and Pharmaceutical Bulletin

ISSN:

0918-6158      

巻:

38

通号:

5

開始ページ:

774

終了ページ:

780

バージョン:

publisher

概要:

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. 続きを見る

URL:

http://hdl.handle.net/2297/43897