Trans-stimulation effects of folic acid derivatives on methotrexate transport by rat renal organic anion transporter, OAT-K1

Ayako Takeuchi, Satohiro Masuda, Hideyuki Saito, Yukiya Hashimoto, Ken Ichi Inui

研究成果: ジャーナルへの寄稿学術誌査読

19 被引用数 (Scopus)

抄録

We examined the pharmacological role of the renal organic anion transporter OAT-K1, which localizes predominantly in the brush-border membranes of proximal straight tubules, in the urinary excretion of methotrexate and the possibility of its contribution to 'folinic acid rescue.' With Madin-Darby canine kidney (MDCK) cells stably transfected with QAT-K1 cDNA, QATK1-mediated methotrexate accumulation was inhibited in the presence of various folic acid derivatives. These derivatives included aminopterin, 5-methyltetrahydrofolic acid, unlabeled methotrexate, folinic acid (citrovorum factor, leucovorin), and folic acid with apparent inhibition constant values of 0.5, 1.2, 1.8, 8.2, and 14.1 μM, respectively. In contrast, 10 μM taurocholic acid and sulfobromophthalein did not inhibit OAT-K1-mediated methotrexate accumulation. In addition, methotrexate efflux was stimulated in the presence of inwardly directed gradients of aminopterin, 5-methyltetrahydrofolic acid, unlabeled methotrexate, folinic acid, and folic acid, but not of uric acid, taurocholic acid, and glutathione, indicating that OAT-K1-mediated methotrexate efflux is stimulated by a folic acid derivatives exchange. In conclusion, OAT-K1 was suggested to enhance the apical efflux of highly accumulated methotrexate in tubular epithelial cells and contribute at least in part to folinic acid rescue by exchanging intracellular methotrexate for extracellular folinic acid.

本文言語英語
ページ(範囲)1034-1039
ページ数6
ジャーナルJournal of Pharmacology and Experimental Therapeutics
293
3
出版ステータス出版済み - 6月 2000
外部発表はい

!!!All Science Journal Classification (ASJC) codes

  • 分子医療
  • 薬理学

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