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 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.
Ullrich
K J
KJ
Max-Planck-Institut für Biophysik, Frankfurt am Main, Germany.
Rumrich
G
G
Burke
T R
TR
Shirazi-Beechey
S P
SP
Lang
H
H
D000818:Animals; D027321:Anion Transport Proteins; D002352:Carrier Proteins / Q000187:drug effects*; D003998:Dicarboxylic Acids / Q000378:metabolism; D004164:Diphosphonates / Q000494:pharmacology*; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008297:Male; D063065:Organophosphonates / Q000494:pharmacology*; D010710:Phosphates / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013431:Sulfates / Q000378:metabolism; D010130:p-Aminohippuric Acid / Q000378:metabolism
D027321:Anion Transport Proteins; D002352:Carrier Proteins; D003998:Dicarboxylic Acids; D004164:Diphosphonates; D063065:Organophosphonates; D010710:Phosphates; D013431:Sulfates; D010130:p-Aminohippuric Acid