POLYSUBSTRATES - SUBSTANCES THAT INTERACT WITH RENAL CONTRALUMINAL PAH, SULFATE, AND NMEN TRANSPORT - SULFAMOYL-CARBOXYLATE, SULFONYLUREA-CARBOXYLATE, THIAZIDE-CARBOXYLATE AND BENZENEAMINO-CARBOXYLATE (NICOTINATE) COMPOUNDS

Some N-containing xenobiotics were recently shown to behave as bisubst rates; that is, they interact with and are transported by both the con traluminal transport system for organic anions (PAH) and the contralum inal transport system for organic cations (NMeN). Thus we determined w hether other classes of N-containing substrates, such as sulfamoyl-, s ulfonylurea-, thiazide- and benzeneamino-carboxylate (nicotinate) comp ounds, amongst them diuretics and other drugs, also interact with both transporters. To test this, we applied the stop-flow peritubular capi llary perfusion method with initial flux measurements and determined a pp. K-i values for these substrates on PAH, sulfate and NMeN transport . We found that the following compounds interact with 1) the PAH trans porter: benzene carboxylates, benzenesulfonylureas and benzenesulfonam ides (as long as their acid pK(a) value is below 9.5). 2) the sulfate transporter: 2-anilinobenzoates, benzenesulfonylureas, polysubstituted sulfamoylbenzoates and some sulfamoylthiazides with electronegative c harge accumulation around an anionic site. 3) the NMeN transporter: an ilinobenzoates, sulfamoylbenzoates and benzenesulfonamides, if they be ar an N-containing pyridine, pyrrolidine, furylmethylamino or thiazide group. There are, however, exceptions when H-bond formation might be responsible for interaction with that transporter. The data confirm th e specificity rule for each transporter and the concept that one and t he same substrate can match the requirements for several transporters. Thus the loop diuretics furosemide and piretanide, the thiazide diure tics hydrochlorothiazide, cyclopenthiazide and bendroflumethiazide and the sulfonylureas tolbutamide, chlorpropamide and torasemide interact with all three tested transport systems for PAH, sulfate and NMeN. Th erefore, they are able to accomplish complex transport interactions wi th different transporters.