Faropenem transport across the renal epithelial luminal membrane via inorganic phosphate transporter Npt1.
We previously showed that the mouse inorganic phosphate transporter Npt1 operates in the hepatic sinusoidal membrane transport of anionic drugs such as benzylpenicillin and mevalonic acid. In the present study, the mechanism of renal secretion of penem antibiotics was examined by using a Xenopus oocyte expression system. Faropenem (an oral penem antibiotic) was transported via Npt1 with a Michaelis-Menten constant of 0.77 +/- 0.34 mM in a sodium-independent but chloride ion-sensitive manner. When the concentration of chloride ions was increased, the transport activity of faropenem by Npt1 was decreased. Since the concentration gradient of chloride ions is in the lumen-to-intracellular direction, faropenem is expected to be transported from inside proximal tubular cells to the lumen. So, we tested the release of faropenem from Xenopus oocytes. The rate of efflux of faropenem from Npt1-expressing oocytes was about 9.5 times faster than that from control water-injected Xenopus oocytes. Faropenem transport by Npt1 was significantly inhibited by beta-lactam antibiotics such as benzylpenicillin, ampicillin, cephalexin, and cefazolin to 24.9, 40. 5, 54.4, and 26.2% of that for the control, respectively. Zwitterionic beta-lactam antibiotics showed lesser inhibitory effects on faropenem uptake than anionic derivatives, indicating that Npt1 preferentially transports anionic compounds. Other anionic compounds, such as indomethacin and furosemide, and the anion transport inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid significantly inhibited faropenem uptake mediated by Npt1. In conclusion, our results suggest that Npt1 participates in the renal secretion of penem antibiotics.
Uchino
H
H
Faculty of Pharmaceutical Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-0934, Japan.
Tamai
I
I
Yabuuchi
H
H
China
K
K
Miyamoto
K
K
Takeda
E
E
Tsuji
A
A
D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D002352:Carrier Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000378:metabolism*; D007700:Kinetics; D007769:Lactams / Q000494:pharmacology; D051379:Mice; D009865:Oocytes / Q000378:metabolism; D028044:Phosphate-Binding Proteins; D010710:Phosphates / Q000378:metabolism; D014981:Xenopus; D047090:beta-Lactams
D000900:Anti-Bacterial Agents; D002352:Carrier Proteins; D007769:Lactams; D028044:Phosphate-Binding Proteins; D010710:Phosphates; D047090:beta-Lactams; C107057:fropenem