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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

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 and Ken-ichi Inui
Journal of Pharmacology and Experimental Therapeutics June 2000, 293 (3) 1034-1039;
Ayako Takeuchi
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Satohiro Masuda
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Hideyuki Saito
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Yukiya Hashimoto
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Ken-ichi Inui
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Abstract

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 OAT-K1 cDNA, OAT-K1-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.

Footnotes

  • Send reprint requests to: Ken-ichi Inui, Ph.D., Department of Pharmacy, Kyoto University Hospital, Sakyo-ku, Kyoto 606-8507, Japan. E-mail: inui{at}kuhp.kyoto-u.ac.jp

  • ↵1 This study was supported by a grant-in-aid for Scientific Research from Ministry of Education, Science, and Culture of Japan and by a grant-in-aid from the Uehara Memorial Foundation.

  • Abbreviations:
    OAT
    organic anion transporter
    oatp1
    organic anion-transporting polypeptide1
    MDCK
    Madin-Darby canine kidney
    • Received January 20, 2000.
    • Accepted February 29, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 293 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 293, Issue 3
1 Jun 2000
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

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 and Ken-ichi Inui
Journal of Pharmacology and Experimental Therapeutics June 1, 2000, 293 (3) 1034-1039;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

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 and Ken-ichi Inui
Journal of Pharmacology and Experimental Therapeutics June 1, 2000, 293 (3) 1034-1039;
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