Hepatic sinusoidal membrane transport of anionic drugs mediated by anion transporter Npt1.
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.
Yabuuchi
H
H
Faculty of Pharmaceutical Sciences, Kanazawa University, 13-1 Takaramachi, Kanazawa 920-0934, Japan.
Tamai
I
I
Morita
K
K
Kouda
T
T
Miyamoto
K
K
Takeda
E
E
Tsuji
A
A
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
D027321:Anion Transport Proteins; D000900:Anti-Bacterial Agents; D002352:Carrier Proteins; D002712:Chlorides; D010400:Penicillin G