Pole of the Kidneys in the Metabolism of Furosemide: Its Inhibition by Probenecid1

The site where furosemide is metabolized and the location where probenecid reduces furosemide metabolism remain poorly defined. The liver appears to play a minor role, and there is indirect evidence suggesting that the kidneys could be responsible for the metabolism of furosemide. To assess the role of the kidneys in the metabolism of furosemide, its intravenous kinetics have been studied in control and anephric rabbits, after the ligation of the renal pedicles. Two additional groups of rabbits, control and anephric, have received probenecid before the administration offurosemide. In the control group, the total clearance of furosemide was 18.65 ± 1.01 mL/ mm per kg; urinary and metabolic clearances of furosemide were 7.95 ± 0.65 and 10.70 ± 1 .1 1 mL/min per kg, respectively. In anephric rabbits, total clearance was reduced by 85% to 2.69 ± 0.26 mL/min per kg (P < 0.001), secondary to the abolition of furosemide renal excretion and to the reduction in metabolic clearance from 10.70 ± 1 .1 1 to 2.69 ± 0.26 mL/min per kg (P < 0.001). The pretreatment with probenecid reduced the total clearance of furosemide by 80%, to 3.62 ± 0.24 mL/min per kg (P < 0.001), because of a reduction of 90 and 75% in urinary and metabolic clearances, respectively. The administration of probenecid to anephric rabbits did not reduce further the metabolic clearance. It is concluded that the kidneys are responsible for 85% of furosemide total clearance, either via excretion (43%) or biotransformation (42%), and that probenecid inhibits both processes.