Interactions of benzylpenicillin and non-steroidal anti-inflammatory drugs with the sodium-dependent dicarboxylate transporter NaDC-3.
Sodium-dependent dicarboxylate transporters located in the basolateral membrane (NaDC-3) of renal proximal tubule cells maintain the driving force for exchange of organic anions and drugs against alpha-ketoglutarate via organic anion transporters OAT1 and OAT3. So far, information on direct interaction of drugs with the cloned NaDC-3 was missing. Here we tested the interaction of non-steroidal anti-inflammatory drugs (NSAIDs) and benzylpenicillin with NaDC-3 cloned from winter flounder (fNaDC-3) and human (hNaDC-3) kidneys. Flufenamate and benzylpenicillin inhibited [14C]succinate uptake in oocytes expressing fNaDC-3. Flufenamate elicited Na(+)-dependent currents in oocytes expressing fNaDC-3 with a reversal potential around -60 mV. Raising extracellular K+ concentration depolarized fNaDC3-expressing oocytes more in the presence of flufenamate than in its absence, an effect not seen with water-injected control oocytes. These findings suggest that flufenamate via interaction with fNaDC-3 increased the K+ conductance. Acetylsalicylate, indomethacin, and salicylate showed small potential-dependent inward currents in fNaDC-3 but not in hNaDC-3 expressing oocytes. Benzylpenicillin induced voltage-dependent inward currents which were Na(+)-dependent in oocytes expressing fNaDC-3. The currents were, however, much smaller than those induced by succinate, reflecting probably a low fit of the monovalent benzylpenicillin to the dicarboxylate binding site. The data show hitherto unknown effects of monovalent anionic drugs on a transporter for divalent di- and tricarboxylates.
Zentrum Physiologie und Pathophysiologie, Abteilung Vegetative Physiologie und Pathophysiologie, Georg-August-Universität Göttingen, Germany.
Birgitta C
BC
Burckhardt
Julia
J
Lorenz
Gerhard
G
Burckhardt
Jürgen
J
Steffgen
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000494:pharmacology*; D003001:Cloning, Molecular; D029382:Dicarboxylic Acid Transporters / Q000235:genetics / Q000378:metabolism*; D005432:Flounder / Q000235:genetics / Q000502:physiology; D005439:Flufenamic Acid / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008564:Membrane Potentials / Q000502:physiology; D009865:Oocytes / Q000378:metabolism; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010400:Penicillin G / Q000378:metabolism / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D014981:Xenopus
D000894:Anti-Inflammatory Agents, Non-Steroidal; D029382:Dicarboxylic Acid Transporters; D029363:Organic Anion Transporters, Sodium-Dependent; C092524:SLC13A2 protein, human; D027981:Symporters; D005439:Flufenamic Acid; D012964:Sodium; D010400:Penicillin G; D011188:Potassium