Furosemide disposition in normal and proteinuric rats: urinary drug-protein binding as a determinant of drug excretion.

We have demonstrated recently that the binding of furosemide (FSM) to urinary proteins causes a decrease in the diuretic response that is proportional to the degree of proteinuria. Further studies were conducted to determine whether urinary drug-protein interactions also altered the renal excretion of FSM. Rats were treated with puromycin aminonucleoside to produce proteinuria. Renal FSM clearance was directly related to urinary protein excretion rate (r = 0.550, P less than .005), a relationship that was more striking when FSM clearance was normalized to glomerular filtration rate (r = 0.781, P less than .001). This relationship was not explained by changes in serum protein concentration or glomerular filtration rate. In order to understand the mechanism of this relationship, normal and nephrotic rats were studied during experimental conditions designed to alter urinary pH. In normal animals urinary acidification induced by HCl infusion produced a profound decrease in renal FSM clearance compared to animals with the more alkaline urine that followed NaHCO2 or acetazolamide pretreatment. This alteration in renal FSM clearance during urinary acidification was not observed in nephrotic animals, despite comparable changes in urinary pH. The diuretic response to FSM did not differ among the normal animals despite the alteration in renal FSM clearance, indicating that the reduction of renal FSM clearance was due to tubular reabsorption of FSM distal to its site of action. These data suggest that urinary drug protein binding may impair the tubular reabsorption of drugs and thereby enhance their renal clearance.