The influence of moderate hypoalbuminaemia on the renal metabolism and dynamics of furosemide in the rabbit.
1. The present study aimed to investigate the influence of hypoalbuminaemia on the pharmacokinetics and pharmacodynamics of furosemide. Hypoalbuminaemia was produced by repeated plasmapheresis, to attain plasma albumin concentrations of 21.6 +/- 0.9 g l-1, compared with 33.0 +/- 0.6 g l-1 in controls (P < 0.001). The per cent of bound furosemide in hypoalbuminaemic rabbits (90.8 +/- 0.7%) was lower than that in control rabbits (97.4 +/- 0.5%, P < 0.001). The kinetics of intravenous furosemide (2.5 mg kg-1) were studied in control (n = 6) and hypoalbuminaemic rabbits (n = 6). 2. To assess the effect of hypoalbuminaemia on extrarenal clearance of furosemide, functional anephria was induced by ligating the renal pedicles of 12 rabbits, which were segregated in two groups, with and without hypoalbuminaemia. 3. In the control group, total, urinary and metabolic clearances of furosemide were 11.8 +/- 1.0, 5.0 +/- 0.4 and 6.8 +/- 0.6 ml min-1 kg-1, respectively. Compared with control rabbits, in hypoalbuminaemic rabbits, total clearance of furosemide increased by 40% (P < 0.001), result of the enhancement of furosemide metabolic clearance (C1m) from 5 to 10 ml min-1 kg-1 (P < 0.01). In hypoalbuminaemic rabbits, urinary excretion of furosemide was reduced by 26% (2451 +/- 115 vs 1818 +/- 134 micrograms h-1, P < 0.01). In anephric rabbits, furosemide total clearance was 1.77 +/- 0.12 ml min-1 kg-1, value not affected by hypoalbuminaemia, confirming that the increase in C1m induced by hypoalbuminaemia occurs in the kidneys. 4. Compared with controls, in hypoalbuminaemic rabbits, the rate of urinary excretion (142 +/- 9 vs 74 +/- 8 ml h-1, P < 0.001) and the rate of excretion of sodium (18.6 +/- 0.9 vs 9.9 +/- 0.9 mmol h-1, P < 0.001) were very much reduced. However, the dose-response curves were not different. 5. In conclusion, hypoalbuminaemia is associated with an increase in renal metabolic clearance of furosemide, possibly because of the increase in furosemide unbound concentration, and a decrease in the diuretic/natriuretic effect of furosemide, secondary to a reduction in furosemide tubular secretion. Thus, albumin facilitates the renal secretion of organic anions but not their metabolism.
Pichette
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Département de Pharmacologie, Faculté de Médicine, Université de Montréal, Québec, Canada.
Geadah
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du Souich
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P
D000818:Animals; D004232:Diuretics / Q000493:pharmacokinetics* / Q000494:pharmacology; D005665:Furosemide / Q000493:pharmacokinetics* / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D008297:Male; D009392:Nephrectomy; D011817:Rabbits; D012709:Serum Albumin / Q000378:metabolism*
D004232:Diuretics; D012709:Serum Albumin; D005665:Furosemide