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Interaction of Alkyl/Arylphosphonates, phosphonocarboxylates and diphosphonates with different anion transport systems in the proximal renal tubule

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Ullrich,  Karl Julius
Emeritusgroup Physiology, Max Planck Institute of Biophysics, Max Planck Society;

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Rumrich,  Gerhard
Emeritusgroup Physiology, Max Planck Institute of Biophysics, Max Planck Society;

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Citation

Ullrich, K. J., Rumrich, G., Burke, T., Shirazi-Beechey, S. P., & Lang, H.-J. (1997). Interaction of Alkyl/Arylphosphonates, phosphonocarboxylates and diphosphonates with different anion transport systems in the proximal renal tubule. Journal of Pharmacology and Experimental Therapeutics, 283(3), 1223-1229.


Cite as: http://hdl.handle.net/21.11116/0000-0008-49C9-4
Abstract
Luminal and contraluminal stop-flow microperfusion was applied, and the apparent Ki 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.Ki < 1 mmol/l), whereas the 2-naphthylphosphonates, phosphonoacetate, pamidronate, alendronate and aminomethanediphosphonates have a moderate affinity (app.Ki, 1.6-6.0 mmol/l). The other compounds tested had a low (app. Ki > 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.Ki </= 0.5 mmol/l), whereas Cl-F-methylphosphonate, 2OH-5NO2-benzyl-phosphonate, 2-naphthylhydroxymethylphosphonate, phosphonoacetate etidonate and clodronate have only a moderate affinity (app.Ki approximately 3 mmol/l). The other tested compounds have a low or no affinity. Dicarboxylate transporter: Among the tested compounds only 3-phosphonopropionate (app.Ki, 4.2 mmol/l) and 4 phosphonobutyrate (app.Ki, 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.