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Research ArticleArticle

Hepatic Sinusoidal Membrane Transport of Anionic Drugs Mediated by Anion Transporter Npt1

Hikaru Yabuuchi, Ikumi Tamai, Kyoko Morita, Tomoko Kouda, Ken-Ichi Miyamoto, Eiji Takeda and Akira Tsuji
Journal of Pharmacology and Experimental Therapeutics September 1998, 286 (3) 1391-1396;
Hikaru Yabuuchi
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Ikumi Tamai
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Kyoko Morita
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Tomoko Kouda
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Ken-Ichi Miyamoto
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Eiji Takeda
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Akira Tsuji
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Abstract

The purpose of our study was to establish the localization of the anion transporter Npt1 in liver and the relevance of Npt1 to carrier-mediated hepatic transport of β-lactam antibiotics. Immunocytochemical examination of mouse liver with antiserum forNpt1 showed basolateral (sinusoidal) membrane localization. Function of Npt1 was characterized in Xenopus laevis oocytes. Injection of in vitro-transcribed cRNA into oocytes resulted in an increased uptake of [14C]benzylpenicillin (PCG). The Npt1-mediated uptake was saturable with a Michaelis constant (Km ) of 0.46 ± 0.18 mM and a maximum rate (Vmax) of 46.6 ± 8.5 pmol/60 min/oocyte, and the uptake of [14C]PCG was independent of Na+ and pH, but dependent on chloride ion. Npt1-mediated [14C]PCG uptake was inhibited by several β-lactam antibiotics and probenecid. Oocytes injected with Npt1-cRNA demonstrated significantly enhanced transport activity for other anionic compounds such as [14C]faropenem, [14C]foscarnet and [3H]mevalonic acid, as well as [14C]PCG, compared with water-injected oocytes. In conclusion, Npt1 is suggested to participate in hepatic sinusoidal membrane transport of organic anions such as β-lactam antibiotics as well as inorganic anions for the efflux from hepatocyte-to-blood direction.

Footnotes

  • Send reprint requests to: Prof. Akira Tsuji, Department of Pharmacobio-Dynamics, Faculty of Pharmaceutical Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-0934, Japan.

  • ↵1 This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture, Japan, by grants from the Japan Health Sciences Foundation, the Drug Innovation Project and the Japan Research Foundation for Clinical Pharmacology and by CREST (Core Research for Evolutional Science and Technology) of Japan Science and Technology Corporation (J.S.T.).

  • Abbreviations:
    PCG
    benzylpenicillin
    HEPES
    N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid
    MES
    2-(N-morpholino)ethanesulfonic acid
    Pi
    inorganic phosphate
    cRNA
    complementary RNA
    Ntcp
    Na+-taurocholate-cotransporting polypeptides
    oatp
    organic anion-transporting polypeptide
    • Received February 27, 1998.
    • Accepted May 11, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 286, Issue 3
1 Sep 1998
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Research ArticleArticle

Hepatic Sinusoidal Membrane Transport of Anionic Drugs Mediated by Anion Transporter Npt1

Hikaru Yabuuchi, Ikumi Tamai, Kyoko Morita, Tomoko Kouda, Ken-Ichi Miyamoto, Eiji Takeda and Akira Tsuji
Journal of Pharmacology and Experimental Therapeutics September 1, 1998, 286 (3) 1391-1396;

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Research ArticleArticle

Hepatic Sinusoidal Membrane Transport of Anionic Drugs Mediated by Anion Transporter Npt1

Hikaru Yabuuchi, Ikumi Tamai, Kyoko Morita, Tomoko Kouda, Ken-Ichi Miyamoto, Eiji Takeda and Akira Tsuji
Journal of Pharmacology and Experimental Therapeutics September 1, 1998, 286 (3) 1391-1396;
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