Vol. 283, Issue 3, 1223-1229, 1997

Interaction of Alkyl/Arylphosphonates, Phosphonocarboxylates and Diphosphonates with Different Anion Transport Systems in the Proximal Renal Tubule

K. J. Ullrich, G. Rumrich, T. R. Burke, S. P. Shirazi-Beechey and H.-J. Lang

Max-Planck-Institut für Biophysik, Frankfurt am Main, Germany (K.J.U., G.R.), Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (T.R.B.), Institute of Biological Sciences, University of Wales, Aberystwyth, UK (S.P.Sh.-B.), HMR-Hoechst AG. Synthetic Research, Frankfurt am Main (H.-J.L.), Germany

Luminal and contraluminal stop-flow microperfusion was applied, and the apparent K_i values (mmol/l) against the luminal phosphate and the contraluminal p-aminohippurate (PAH), sulfate and dicarboxylate transport systems were evaluated. Luminal phosphate transporter: Among the 20 compounds tested only phosphonoformate (foscarnet), etidronate, and clodronate have a good affinity (app.K_i < 1 mmol/l), whereas the 2-naphthylphosphonates, phosphonoacetate, pamidronate, alendronate and aminomethanediphosphonates have a moderate affinity (app.K_i, 1.6-6.0 mmol/l). The other compounds tested had a low (app.K_i > 6 mmol/l) or no affinity. Contraluminal PAH transporter: The hydrophobic phenyl-, benzyl- or 2-naphthylphosphonates have good to moderate affinity, whereas the less hydrophobic alkylphosphonates, the phosphonocarboxylates (except 4-phosphonobutyrate) and all tested diphosphonates show no interaction. Sulfate transporter: 2-Naphthylmethylphosphonate and 2-naphthylmethyldifluorophosphonate have a good affinity (app.K_i  0.5 mmol/l), whereas Cl-F-methylphosphonate, 2OH-5NO₂-benzyl-phosphonate, 2-naphthylhydroxymethylphosphonate, phosphonoacetate etidonate and clodronate have only a moderate affinity (app.K_i  3 mmol/l). The other tested compounds have a low or no affinity. Dicarboxylate transporter: Among the tested compounds only 3-phosphonopropionate (app.K_i, 4.2 mmol/l) and 4 phosphonobutyrate (app.K_i, 7.0 mmol/l) interact with this transporter. Thus, we might conclude that in the submillimolar range only phosphonoformate (foscarnet), etidronate and clodronate inhibit luminal phosphate transport. As predictable from previous structure-activity studies for the contraluminal PAH, sulfate and dicarboxylate transporters the alkyl/arylphosphonates and the phosphonocarboxylates interact with these transporters according to their hydrophobicity and charge distribution. Among the seven diphosphonates tested, only etidronate and clodronate have a moderate affinity to the sulfate transporter, whereas the aminodiphosphonates have no (or low) affinity to any of the contraluminal anion transporters.