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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Rat Multispecific Organic Anion Transporter 1 (rOAT1) Transports Zidovudine, Acyclovir, and Other Antiviral Nucleoside Analogs

Saiko Wada, Minoru Tsuda, Takashi Sekine, Seok Ho Cha, Miyako Kimura, Yoshikatsu Kanai and Hitoshi Endou
Journal of Pharmacology and Experimental Therapeutics September 2000, 294 (3) 844-849;
Saiko Wada
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Minoru Tsuda
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Takashi Sekine
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Seok Ho Cha
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Miyako Kimura
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Yoshikatsu Kanai
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Hitoshi Endou
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Abstract

Organic anion transporter 1 (OAT1) is ap-aminohippurate/dicarboxylate exchanger that plays a primary role in the tubular secretion of endogenous and exogenous organic anions. OAT1 is located in the basolateral membrane of the proximal tubular cells and mediates the uptake of various organic anions from the peritubular fluid. In this study, we investigated the transport of antiviral nucleoside analogs via rat OAT1 (rOAT1) using a heterologous expression system in Xenopus laevisoocytes. Oocytes injected with rOAT1 cRNA showed significantly higher uptake of zidovudine (AZT) and acyclovir (ACV) than control oocytes. rOAT1-mediated uptake of AZT and ACV was probenecid-sensitive and increased by the outwardly directed gradient of glutarate. The affinity of rOAT1 for AZT and ACV was determined to be 68 and 242 μM, respectively. Five other antiviral agents that we studied (zalcitabine, didanosine, lamivudine, stavudine, and trifluridine) were also shown to be transported by rOAT1, whereas foscarnet, a phosphate analog, was not. The aforementioned nucleoside analogs lack a typical anionic group and are not very hydrophobic. This study demonstrates extension of the substrate spectrum of rOAT1 and provides a molecular basis for the pharmacokinetics of antiviral nucleoside analogs.

Footnotes

  • Send reprint requests to: Dr. Hitoshi Endou, Department of Pharmacology and Toxicology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan. E-mail:endouh{at}kyorin-u.ac.jp

  • ↵1 This work was supported in part by grants from the Japanese Ministry of Education Science, Sports and Culture, the Uehara Memorial Foundation, Grants-in-Aids for Scientific Research and High-Tech Research Center from the Science Research Promotion Fund of the Japan Private School Promotion Foundation, Grants-in-Aid from the Tokyo Biochemical Research Foundation, and Research on Health Sciences focusing on Drug Innovation from The Japan Health Sciences Foundation.

  • Abbreviations:
    PAH
    p-aminohippurate
    OAT1
    organic anion transporter 1
    rOAT1
    rat OAT1
    AZT
    zidovudine
    ACV
    acyclovir
    ddC
    zalcitabine
    ddI
    didanosine
    d4T
    stavudine
    BBB
    blood-brain barrier
    • Received February 28, 2000.
    • Accepted May 25, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 294 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 294, Issue 3
1 Sep 2000
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Rat Multispecific Organic Anion Transporter 1 (rOAT1) Transports Zidovudine, Acyclovir, and Other Antiviral Nucleoside Analogs

Saiko Wada, Minoru Tsuda, Takashi Sekine, Seok Ho Cha, Miyako Kimura, Yoshikatsu Kanai and Hitoshi Endou
Journal of Pharmacology and Experimental Therapeutics September 1, 2000, 294 (3) 844-849;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Rat Multispecific Organic Anion Transporter 1 (rOAT1) Transports Zidovudine, Acyclovir, and Other Antiviral Nucleoside Analogs

Saiko Wada, Minoru Tsuda, Takashi Sekine, Seok Ho Cha, Miyako Kimura, Yoshikatsu Kanai and Hitoshi Endou
Journal of Pharmacology and Experimental Therapeutics September 1, 2000, 294 (3) 844-849;
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