Role of plasma protein binding on renal metabolism and dynamics of furosemide in the rabbit.

To investigate the influence of furosemide plasma protein binding on its kinetics and dynamics, the kinetics of furosemide was studied in the presence of a protein binding displacer, warfarin, and in hypoalbuminemic rabbits. Compared with controls, in anesthetized rabbits pretreated with warfarin, the unbound fraction of furosemide increased from 1.8 +/- 0.4% to 7.0 +/- 0.4% (p <.001), and its metabolic clearance increased by 30%, whereas furosemide urinary excretion decreased by 48% (p <.05). Experiments in nephrectomized rabbits showed that the increase in metabolic clearance was secondary to an increase in its renal metabolic clearance (p <.05). Compared with controls, in warfarin pretreated rabbits, sodium excretion and diuresis were decreased by 30% (p <.05). However, when furosemide was injected mixed with albumin, warfarin-induced kinetic and dynamic alterations of furosemide were reversed. Compared with control rabbits, in conscious hypoalbuminemic rabbits, furosemide unbound fraction was enhanced from 1.2 +/- 0.1% to 5.5 +/- 0.5% (p <. 001), and its urinary excretion, diuresis, and sodium excretion were reduced by 22% (p <.05). The administration of warfarin to hypoalbuminemic rabbits further increased the fraction of unbound furosemide, and diminished its urinary excretion and diuretic effect. In conclusion, 1) binding of furosemide to plasma proteins, and not albumin per se, facilitates its renal secretion and pharmacological response; 2) the decrease in furosemide binding, secondary to drug displacement and/or hypoalbuminemia, can be a cause of resistance to the diuretic; and 3) when furosemide binding is decreased, the administration of furosemide mixed with albumin enhances its renal secretion and diuretic effect.