Faropenem transport across the renal epithelial luminal membrane via inorganic phosphate transporter Npt1

We previously showed that the mouse inorganic phosphate transporter Npt1 op erates in the hepatic sinusoidal membrane transport of anionic drugs such a s benzylpenicillin and mevalonic acid. In the present study, the mechanism of renal secretion of penem antibiotics was examined by using a Xenopus ooc yte 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 ch loride ions was increased, the transport activity of faropenem by Npt1 was decreased. Since the concentration gradient of chloride ions is in the lume n-to-intracellular direction, faropenem is expected to be transported from inside proximal tubular cells to the lumen. So, we tested the release of fa ropenem from Xenopus oocytes, The rate of efflux of faropenem from Npt1-exp ressing oocytes was about 9.5 times faster than that from control water-inj ected Xenopus oocytes, Faropenem transport by Npt1 was significantly inhibi ted by beta-lactam antibiotics such as benzylpenicillin, ampicillin, cephal exin, and cefazolin to 24.9, 40.5, 54.4, and 26.2% of that for the control, respectively. Zwitterionic beta-lactam antibiotics showed lesser inhibitor y effects on faropenem uptake than anionic derivatives, indicating that Npt 1 preferentially transports anionic compounds. Other anionic compounds, suc h as indomethacin and furosemide, and the anion transport inhibitor 4,4'-di isothiocyanostilbene-2,2'-disulfonic acid significantly inhibited faropenem uptake mediated by Npt1, In conclusion, our results suggest that Npt1 part icipates in the renal secretion of penem antibiotics.