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 (K_m ) 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.