Dose-dependent pharmacokinetics of furosemide in the rat

The pharmacokinetics of furosemide were investigated in the rat at doses of 10 and 40 mg kg-1 corresponding to doses of 80 and 320 mg given to humans based on body surface area. A three-compartment open model with renal excretion taking place from the shallow peripheral compartment gave the best fit to the data. The terminal half-life of furosemide was found to change from 29 min for the 10 mg kg-1 dose to 49 min for the 40 mg kg-1 dose. This change could be detected as a change in the apparent volume of distribution caused by decreased protein binding at increasing plasma concentrations of furosemide. The total plasma clearance did not change significantly although metabolic and renal clearance both changed. The renal clearance was found to be dependent on the free fraction of furosemide in plasma and thus increased with increasing plasma concentrations. The metabolic clearance decreased with increasing dose indicating a saturable metabolism of furosemide.