title: Hepatic sinusoidal membrane transport of anionic drugs mediated by anion transporter Npt1.
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 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.
authors.affiliation: Faculty of Pharmaceutical Sciences, Kanazawa University, 13-1 Takaramachi, Kanazawa 920-0934, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Yabuuchi
authors.forename: I
authors.initials: I
authors.lastname: Tamai
authors.forename: K
authors.initials: K
authors.lastname: Morita
authors.forename: T
authors.initials: T
authors.lastname: Kouda
authors.forename: K
authors.initials: K
authors.lastname: Miyamoto
authors.forename: E
authors.initials: E
authors.lastname: Takeda
authors.forename: A
authors.initials: A
authors.lastname: Tsuji
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D001692:Biological Transport; D002352:Carrier Proteins / Q000032:analysis / Q000502:physiology*; D002712:Chlorides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006863:Hydrogen-Ion Concentration; D008099:Liver / Q000378:metabolism*; D051379:Mice; D010400:Penicillin G / Q000493:pharmacokinetics; D014982:Xenopus laevis
chemical_list: D027321:Anion Transport Proteins; D000900:Anti-Bacterial Agents; D002352:Carrier Proteins; D002712:Chlorides; D010400:Penicillin G