HEPATIC SINUSOIDAL MEMBRANE-TRANSPORT OF ANIONIC DRUGS MEDIATED BY ANION TRANSPORTER NPT1

The purpose of our study was to establish the localization of the anio n transporter Npt1 in liver and the relevance of Npt1 to carrier-media ted hepatic transport of beta-lactam antibiotics. Immunocytochemical e xamination 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 [C-14]benzylpenicillin (PC G). 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 pmo l/60 min/oocyte, and the uptake of [C-14]PCG was independent of Na+ an d pH, but dependent on chloride ion. Npt1-mediated [C-14]PCG uptake wa s inhibited by several beta-lactam antibiotics and probenecid. Oocytes injected with Npt1-cRNA demonstrated significantly enhanced transport activity for other anionic compounds such as [C-14]faropenem, [C-14]f oscarnet and [H-3]mevalonic acid, as well as [C-14]PCG, compared with water-injected oocytes. In conclusion, Npt1 is suggested to participat e in hepatic sinusoidal membrane transport of organic anions such as b eta-lactam antibiotics as well as inorganic anions for the efflux from hepatocyte-to-blood direction.