Furosemide dynamics in conscious rabbits: Modulation by angiotensin II

Homsy, Walid; Marleau, Sylvie; P, du Souich

doi:10.1007/bf00878676

Cited by 3 publications

(1 citation statement)

References 34 publications

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“…All the rabbits received furosemide 2.5 mg kg-', i.v. This dose was based upon the fact that the kinetics of furosemide injected intravenously are first order up to doses of 10 mg kg' (Homsy et al, 1995).…”

Section: Experimental Protocolmentioning

confidence: 99%

The influence of moderate hypoalbuminaemia on the renal metabolism and dynamics of furosemide in the rabbit

Pichette

Geadah

Souich

1996

British J Pharmacology

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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 1', compared with 33.0+0.6 g 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-') 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 1.8 + 1.0, 5.0 + 0.4 and 6.8 + 0.6 ml min-' kg-', 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 (Clm) from 5 to 10 ml min-' kg-' (P<0.01). In hypoalbuminaemic rabbits, urinary excretion of furosemide was reduced by 26% (2451 + 115 vs 1818 + 134 pg h-', P<0.01). In anephric rabbits, furosemide total clearance was 1.77+0.12 ml min-' kg-', value not affected by hypoalbuminaemia, confirming that the increase in Clm 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-', P<0.001) and the rate of excretion of sodium (18.6+0.9 vs 9.9+0.9 mmol h-', 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.

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Section: Experimental Protocolmentioning

confidence: 99%

The influence of moderate hypoalbuminaemia on the renal metabolism and dynamics of furosemide in the rabbit

Pichette

Geadah

Souich

1996

British J Pharmacology

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Considerations on pharmacodynamics and pharmacokinetics: Can everything be explained by the extent of drug binding to its receptor?

Castañeda‐Hernández¹,

Granados‐Soto²

2000

Can. J. Physiol. Pharmacol.

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It is frequently assumed that pharmacological responses depend solely on the extent of drug binding to its receptor according to the occupational theory. It is therefore presumed that the intensity of the effect is determined by drug concentration at its receptor site, yielding a unique concentration-effect relationship. However, when dependence, abstinence, and tolerance phenomena occur, as well as for pharmacological responses in vivo that are modulated by homeostatic mechanisms, the rate of drug input shifts the concentration-effect relationship. Hence, such responses cannot be explained on the sole basis of the extent of drug binding to its receptor. Information on the cellular and molecular processes involved in the generation of abstinence, dependence, and tolerance will undoubtedly result in the development of pharmacodynamic models allowing a satisfactory explanation of drug effects modulated by these phenomena. Notwithstanding, integrative physiology concepts are required to develop pharmacokinetic-pharmacodynamic models allowing the description of drug effects in an intact organism. It is therefore important to emphasize that integrative physiology cannot be neglected in pharmacology teaching and research, but should be considered as an equally valuable tool as molecular biology and other biomedical disciplines for the understanding of pharmacological effects.

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Role of the kidneys in the metabolism of furosemide

Pichette

Souich

1996

Journal of the American Society of Nephrology

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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 of furosemide. In the control group, the total clearance of furosemide was 18.65 +/- 1.01 mL/ min per kg; urinary and metabolic clearances of furosemide were 7.95 +/- 0.65 and 10.70 +/- 1.11 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 +/- 1.11 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.

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Furosemide dynamics in conscious rabbits: Modulation by angiotensin II

Cited by 3 publications

References 34 publications

The influence of moderate hypoalbuminaemia on the renal metabolism and dynamics of furosemide in the rabbit

The influence of moderate hypoalbuminaemia on the renal metabolism and dynamics of furosemide in the rabbit

Considerations on pharmacodynamics and pharmacokinetics: Can everything be explained by the extent of drug binding to its receptor?

Role of the kidneys in the metabolism of furosemide

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