Resistance of proteinuric rats to furosemide: Urinary drug protein binding as a determinant of drug effect

The effect of drug binding to urinary proteins on the diuretic response to furosemide was assessed in normal and nephrotic rats. Nephrosis was induced by treating Sprague-Dawley rats with puromycin aminonucleoside. Binding of furosemide to urinary proteins was found to range from 60 to 95% depending on the concentration of urinary protein. The diuretic response to furosemide reaching the renal tubular lumen was inversely correlated with the degree of proteinuria, a finding that was independent of serum protein concentration of glomerular filtration rate. These data suggest that the binding of furosemide to urinary protein decreases the diuretic effect of furosemide and that drug-protein interactions of this type may also be important in modulating the activity of other lumenally-active drugs or endogenous substances exhibiting a high degree of protein binding. The binding of furosemide to urinary protein may explain the refractoriness of some patients with proteinuria to this agent.