INTERACTION OF ALKYL ARYLPHOSPHONATES, PHOSPHONOCARBOXYLATES AND DIPHOSPHONATES WITH DIFFERENT ANION TRANSPORT-SYSTEMS IN THE PROXIMAL RENAL TUBULE/

Luminal and contraluminal stop-flow microperfusion was applied, and th e apparent K-i values (mmol/l) against the luminal phosphate and the c ontraluminal p-aminohippurate (PAH), sulfate and dicarboxylate transpo rt systems were evaluated. Luminal phosphate transporter: Among the 20 compounds tested only phosphonoformate (foscarnet), etidronate, and c lodronate have a good affinity (app.K-i, < 1 mmol/l), whereas the 2-na phthylphosphonates, phosphonoacetate, pamidronate, alendronate and ami nomethanediphosphonates have a moderate affinity (app.K-i, 1.6-6.0 mmo l/l). The other compounds tested had a. low (app.K-i > 6 mmol/l) or no affinity. Contraluminal PAH transporter: The hydrophobic phenyl-, ben zyl- or 2-naphthylphosphonates have good to moderate affinity, whereas the less hydrophobic alkylphosphonates, the phosphonocarboxylates (ex cept 4-phosphonobutyrate) and all tested diphosphonates show no intera ction. Sulfate transportee 2-Naphthylmethylphosphonate and 2-naphthylm ethyldifluorophosphonate have a good affinity (app.K-i less than or eq ual to 0.5 mmol/l), whereas Cl-F-methylphosphonate, 20H-5NO(2)-benzyl- phosphonate, 2-naphthylhydroxymethylphosphonate, phosphonoacetate etid onate and clodronate have only a moderate affinity (app.K-i approximat e to 3 mmol/l). The other tested compounds have a low or no affinity. Dicarboxylate transporter: Among the tested compounds only 3-phosphono propionate (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), etidrona te and clodronate inhibit luminal phosphate transport. As predictable from previous structure-activity studies for the contraluminal PAH, su lfate and dicarboxylate transporters the alkyl/arylphosphonates and th e phosphonocarboxylates interact with these transporters according to their hydrophobicity and charge distribution. Among the seven diphosph onates 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.