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A preclinical pharmacokinetic and pharmacodynamic approach to determine a dose of spironolactone for treatment of congestive heart failure in dog
Author(s) -
GUYONNET J.,
ELLIOTT J.,
KALTSATOS V.
Publication year - 2010
Publication title -
journal of veterinary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.527
H-Index - 60
eISSN - 1365-2885
pISSN - 0140-7783
DOI - 10.1111/j.1365-2885.2009.01130.x
Subject(s) - spironolactone , aldosterone , medicine , endocrinology , pharmacodynamics , chemistry , fractional excretion of sodium , pharmacokinetics , heart failure , urine , pharmacology
Guyonnet, J., Elliott, J., Kaltsatos, V. A preclinical pharmacokinetic and pharmacodynamic approach to determine a dose of spironolactone for treatment of congestive heart failure in dog. J. vet. Pharmacol. Therap. 33 , 260–267. Fifteen Beagle dogs were used to describe the anti‐aldosterone effect of spironolactone (0, 0.8, 2 and 8 mg/kg) in a hyperaldosteronism model. The magnitude of the aldosterone response observed in this model was very similar to the one described in a dog with congestive heart failure (CHF). Each dog was allocated to a treatment group according to a 5 × 5 Latin square crossover design for five periods with a washout period of 7 days between each period. A maximal possible effect (E max ) model was employed to determine the basic pharmacodynamic parameters of spironolactone, measured by high‐performance liquid chromatography, in antagonizing the renal effects of aldosterone. The change in urinary sodium / potassium ratio in response to a single dose of aldosterone was calculated. The inhibition of this response by oral spironolactone administration was assessed. Aldosterone alone decreased sodium excretion by approximately 35% and urinary potassium concentrations increased by 25%, whereas the urine volume decreased, as expected. The effect of aldosterone on the Na + /K + ratio was completely reversed (88% inhibition) at a dose of 2 mg spironolactone/kg, while at the dose of 0.8 mg/kg, partial reversal was seen (27.5% inhibition). Urine flow rate was not significantly modified by either aldosterone treatment or aldosterone with spironolactone. The dose of spironolactone required to inhibit the action of aldosterone by 50% (ED 50 ) was estimated to be 1.08 ± 0.28 mg/kg. The E max was a ratio of 1.089 ± 0.085, close to the observed value in negative control group (1.00 ± 0.18). The proposed spironolactone dose using this E max model was 2 mg/kg b.w. once daily for the management.