To investigate the influence of furosemide plasma protein binding on its ki
netics 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, t
he 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 furose
mide urinary excretion decreased by 48% (p < .05), Experiments in nephrecto
mized rabbits showed that the increase in metabolic clearance was secondary
to an increase in its renal metabolic clearance (p < .05). Compared with c
ontrols, in warfarin pretreated rabbits, sodium excretion and diuresis were
decreased by 30% (p < .05). However, when furosemide was injected mixed wi
th 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 excret
ion were reduced by 22% (p < .05), The administration of warfarin to hypoal
buminemic rabbits further increased the fraction of unbound furosemide, and
diminished its urinary excretion and diuretic effect. In conclusion, 1) bi
nding of furosemide to plasma proteins, and not albumin per se, facilitates
its renal secretion and pharmacological response; 2) the decrease in furos
emide binding, secondary to drug displacement and/or hypoalbuminemia, can b
e 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.