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Vol. 286, Issue 3, 1391-1396, September 1998

Hepatic Sinusoidal Membrane Transport of Anionic Drugs Mediated by Anion Transporter Npt11

Hikaru Yabuuchi, Ikumi Tamai, Kyoko Morita, Tomoko Kouda, Ken-Ichi Miyamoto, Eiji Takeda and Akira Tsuji

Faculty of Pharmaceutical Sciences, Kanazawa University, 13-1 Takaramachi, Kanazawa 920-0934 (H.Y., I.T., A.T.), and Department of Clinical Nutrition, School of Medicine, Tokushima University, Kuramoto-Cho 3, Tokushima 770-0042 (K.Mo., T.K., K.Mi., E.T.), Japan

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 beta -lactam antibiotics. Immunocytochemical examination of mouse liver with antiserum for Npt1 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 beta -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 beta -lactam antibiotics as well as inorganic anions for the efflux from hepatocyte-to-blood direction.

0022-3565/98/2863-1391$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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