Disposition of Tritium-Labeled Spirolactones in the Dog

Sadée, Wolfgang; Riegelman, Sidney; Jones, Sean

doi:10.1002/jps.2600610721

Cited by 14 publications

(3 citation statements)

References 9 publications

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“…It is rapidly and completely metabolized to several active metabolites (i.e. 7α‐thio‐spirolactone, 7α‐thiomethyl‐spirolactone, 6β‐hydroxy‐7α‐thiomethyl‐Spirolactone and canrenone) (Sadee et al. , 1972).…”

Section: Introductionmentioning

confidence: 99%

A preclinical pharmacokinetic and pharmacodynamic approach to determine a dose of spironolactone for treatment of congestive heart failure in dog

Guyonnet

Elliott

Kaltsatos

2009

Journal of Veterinary Pharmacology and Therapeutics

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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 x 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.

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Section: Introductionmentioning

confidence: 99%

A preclinical pharmacokinetic and pharmacodynamic approach to determine a dose of spironolactone for treatment of congestive heart failure in dog

Guyonnet

Elliott

Kaltsatos

2009

Journal of Veterinary Pharmacology and Therapeutics

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“…Apres administration de canrenone, les valeurs des principaux parametres pharmacocinetiques sont comparables Ii celles rapportees dans la litterature (4)(5)(6)(8)(9)(10) La variabilite entre sujet est plus importante au niveau du profil d'absorption qu'au cours des deux autres phases decelees ; une telle variabilite dans I'absorption a ete couramment observee que ce soit apres administration de canrenone ou de spironolactone (4-6, 8, 9). En effet, la canrenone se transforme en acide canrenoique selon un equilibre reversible fortement dependant du pH (2); iI se pourrait que les processus de lactonisation et d'hydrolyse aient lieu dans Ie tube digestif, avant I'absorption.…”

Section: Discussion Et Conclusionunclassified

“…Send reprint requests to: F. Bressolle De nombreuses informations sur la pharmacocinetique de la canrenone sont apportees par les travaux realises apres administration de spironolactone; en effet, la methode de dosage de la canrenone etant rapide, specifique et sensible ce sont Ie plus sou vent les canrenonemies qui sont rnesurees, que ce soit apres administration de spironolactone (5-10), de canrenoate de potassium (3,8,10) ou de canrenone (4,6,9,II).…”

Section: Introductionunclassified

Biodisponibilité relative chez l’homme de deux formes pharmaceutiques à base de canrénone

Bressolle

Brès

Faure

et al. 1986

European Journal of Drug Metabolism and Pharmacokinetics

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The relative bioavailability of 100 mg canrenone capsules and the commercial 50 mg capsules has been determined in 12 healthy male subjects. The study was conducted in a cross over design. After the absorption phase canrenone plasma concentrations followed a biexponential decay. The half lives of the three phases observed were respectively 40.7 +/- 21.7 min, 1.94 +/- 0.558 hr and 18.5 +/- 3.93 hr after administration of a 100 mg capsules; they were respectively 31.8 +/- 14 min, 1.64 +/- 0.513 hr and 16.1 +/- 3.09 hr after administration of two 50 mg capsules. These values were similar to those reported in man. Bioequivalence of the two forms tested was ascertained by a two way analysis of variance and by the Westlake symmetrical confidence interval (95%). Peak plasma levels, Cmax, time to reach the peak, tmax, and the rate constant of absorption showed great inter and intra individual variations. In vivo hydrolysis of canrenone into canrenoic acid and subsequent lactonization of the acid are pH-dependent and could give rise to these variations if occurring before absorption.

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Zur Spezifität der Bestimmung von Canrenon in biologischen Flüssigkeiten

Stüber

Mutschler

Steinbach

1981

Archiv der Pharmazie

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Es wurde eine vergleichende Untersuchung von Canrenon und weiteren Spironolacton-Metaboliten mit verschiedenen analytischen Nachweisverfahren (Fluorimetrie, GC-MS, HPLC) durchgefuhrt.Die Notwendigkeit einer spezifischen Bestimmung von Canrenon in Plasma und Urin, die insbesondere mit HPLC-Verfahren moglich ist, wird diskutiert. Determination of Canrenone in Biological FlnidsA comparative study of canrenone and further spironolactone metabolites was carried out with the aid of various analytical procedures (Fluorimetry, GLC-MS, HPLC). The need for a specific method for the determination of canrenone in plasma und urine is discussed.Spironolacton wird als Aldosteronantagonist in der Diuretika-Therapie eingesetzt. In der Literatur sind neben Arbeiten mit radioaktiv markierten MateriaP3) fluorimetrische, gaschromatographische und hochdruckflussigkeitschromatographische Verfahren zur quantitativen Bestimmung von Canrenon, dem Hauptmetaboliten, in Plasma und Urin beschrieben6lo). Bei der vergleichenden Bewertung der Literaturdaten wird die Diskrepanz der Ergebnisse bei den verschiedenen Analysenverfahren deutlich. Spironolacton unterliegt einer intensiven Biotransformation, von 33 % der Dosis, die bei einer Messung der Gesamtradioaktivitat renal eliminiert werden2) , machen Canrenon, Canrenoinsaure und das Esterglucuronid nur etwa ein Drittel dieser Fraktion aus') .Weitere Hauptmetabolite stellen die am Schwefel oxidierten und in 66-und in l5a-Stellung hydroxylierten Substanzen dar. In Abb. 1 sind die Hauptmetabolisierungswege von Spironolacton zusammengefaBt. Im folgenden wird uber eine vergleichende Untersuchung zur Spezifitat verschiedener Canrenon-Bestimmungsmethoden berichtet.

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Disposition of Tritium-Labeled Spirolactones in the Dog

Cited by 14 publications

References 9 publications

A preclinical pharmacokinetic and pharmacodynamic approach to determine a dose of spironolactone for treatment of congestive heart failure in dog

A preclinical pharmacokinetic and pharmacodynamic approach to determine a dose of spironolactone for treatment of congestive heart failure in dog

Biodisponibilité relative chez l’homme de deux formes pharmaceutiques à base de canrénone

Zur Spezifität der Bestimmung von Canrenon in biologischen Flüssigkeiten

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