Effect of spironolactone on excretion of 3H-digoxin and its metabolites in rats

doi:10.1016/0014-2999(74)90168-X

European Journal of Pharmacology

Volume 29, Issue 1, November 1974, Pages 43-51

https://doi.org/10.1016/0014-2999(74)90168-X Get rights and content

Abstract

Spironolactone increased the total excretion of radioactivity in female rats given specific labelled ³H-digoxin. This increase was due to enhanced fecal excretion while urinary elimination of radioactivity and blood tritium levels were reduced. The ratio of total excreted digoxin to its metabolites which was measured by paper and thin-layer chromatography was changed from 28%: 72% under control conditions to 2% : 98% during spironolactone treatment. This increased excretion of metabolites mainly concerned the aqueous soluble compounds, the digoxigenin monodigitoxoside and the digoxigenin. The excretion of the genin was enhanced in urine only.

After metabolism of ³H-digoxin could still be observed 25 days after discontinuation of treatment with spironolactone. It is concluded that in rats spironolactone increased the metabolism of digoxin by induction of hepatic microsomal enzyme activity.

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The effect of the antimineralocorticoid, spironolactone on the hepatic synthesis of polar metabolites of aldosterone in male rats
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A single, acute, pharmacological dose of spironolactone reduced the total radioactivity (d.p.m./g) in both the homogenates and the cytosol fractions of the liver and kidney, 30 min after the sc injection of 0.1 μg [³H]-aldosterone, by approximately half in male rats. The liver and kidney homogenates in the spironolactone-treated rats contained 18 and 1.6% of the total injected [³H]-radioactivity compared to 40 and 2.4%, respectively, in the control rats.
In the liver, Sephadex DEAP-LH-20 column chromatography demonstrated that the spironolactone treatment led to (i) an increase in the synthesis of mono- and di-sulfated conjugates of aldosterone and its metabolites and (ii) to a decrease in the quantities of polar neutral metabolites of aldosterone (NMA). In the kidney, the spironolactone treatment led to decreased quantities of the polar NMA, the acidic metabolites of aldosterone and the sulfate and glucuronide conjugates. No changes in the quantities of unmetabolized aldosterone in the target tissue, the kidney, were observed. Interestingly, the half-life for aldosterone in the plasma, 12.5 min, was not altered following the spironolactone treatment.
The polar NMA isolated from both the liver and kidney cytosol were resolved by high pressure liquid chromatography (HPLC) into several peaks of metabolites (at least 9). The retention times of most of the NMA separated from the kidney cytosol were identical to those separated from the liver cytosol and represented the major portion of the polar metabolites of aldosterone in these tissues. Four main groups of metabolites with decreasing polarity were eluted from the HPLC. Following spironolactone treatment, the quantities of the individual peaks of NMA in both the liver, and kidney were significantly reduced. Of major interest in the liver, the quantities of highly polar NMA in group 1 were pronouncedy reduced following spironolactone treatment. These effects of spironolactone on the metabolism of aldosterone may be related to the mechanism of action of the anti-mineralocorticoid, spironolactone.
2 Heterosteroids and Drug Research
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Heterosteroids have recently received much attention. The altered chemical and physical properties are envisaged to lead to the discovery of new substances having the potential of providing some useful drugs. Heterosteroids are divided into nucleo- and extranucleo-categories. The former contain heteroatoms in the nucleus, whereas in the latter, heteroatoms form part of a fused or spiro ring system, an attached group, or a side chain. The facets of heterosteroids discussed in this chapter pertain to adrenocorticoids, anti-mineralocorticoids, anabolics, androgen antagonists and biosynthesis inhibitors, oestrogenic, anti-oestrogenic, progestational, anti-progestational, anti-fertility, catatoxic, cardiac, anti-lipemic, central nervous system acting, neuromuscular blocking, local anaesthetic, diagnostic, antimicrobial, anti-neoplastic, and miscellaneous agents. Medicinal chemists have ventured to modify the corticosteroid structures in different ways and many highly successful drugs have resulted. The chapter focuses on hetero modifications and some closely related aspects. Certain hetero analogues of the mineralocorticoid deoxycorticosterone have been prepared and examined. Some of the synthetic compounds are adrenal inhibitors and anticatabolics.
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Serum and tissue digoxin concentrations were estimated by radioimmunoassay in maternal and fetal animals at various times following the injection of pregnant rats, on Days 19 or 20 of gestation, with digoxin (0.1 mg/kg iv). Maternal serum digoxin concentrations were 3.5 to 5 times greater than corresponding fetal concentrations during the early period of sampling (2–10 min) and ranged from 1.8- to 2.7-fold higher for the remainder of each experiment. The elimination of digoxin from maternal serum followed a biexponential pattern ( $t_{12} α = 0.36 hr; t_{12} β = 3.52 hr; K_{el} = 0.39 hr^{−1}$ ) and was similar to that observed in placental tissue and the fetal circulation. Maternal tissue concentrations of digoxin were highest in the liver followed in descending order by the skeletal muscle, heart, and kidney. The distribution pattern in fetal tissues differed significantly as indicated: heart > kidney > liver. These data have demonstrated that digoxin is rapidly transferred across the placenta of the pregnant rat. Differences in the fetal/maternal tissue distribution patterns of the drug may reflect developmental influences upon tissue binding and/or regional perfusion.
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Lack of interaction of spironolactone with ouabain in guinea pig isolated heart muscle preparations
1978, European Journal of Pharmacology
The effect of spironolactone on ouabain action was studied in experiments on guinea pig isolated heart muscle preparations. There was no effect of spironolactone on the ouabain-induced positive inotropic or toxic effects in isolated papillary muscles. This was accompanied by a lack of spironolactone effect on myocardial ouabain uptake. Only rather high spironolactone concentrations (1 × 10⁻⁴M) led to a reduced cardiac ouabain uptake (about 10%). The subcellular distribution pattern of ouabain, however, remained unchanged under these conditions. Studies on ouabain binding to a cardiac NaK-ATPase supported the conclusion that a direct interaction of spironolactone and cardiac glycosides at the myocardium could be ruled out.

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Effect of spironolactone on excretion of 3H-digoxin and its metabolites in rats

Abstract

Biochem. Pharmacol.

J. Pharm. Sci.

Toxicol. Appl. Pharmacol.

Effects of pretreatment with spironolactone on pharmacokinetics of 4′′′-Methyldigoxin in rats

Naunyn Schmiedeb. Arch. Pharmacol.

Metabolism of digoxigenin, digoxigeninmonodigitoxoside and digoxigeninbis-digitoxoside in rats

Naunyn Schmiedeb. Arch. Pharmacol.

A study of the factors effecting the aluminiu oxide-trihydroxyindole procedure for the analysis of catecholamines

J. Pharmacol. Exptl. Therap.

The distribution of digitalis glycosides and their metabolites within the body of the rat

J. Pharmacol. Exptl. Therap.

Possible mechanism of the prevention of digitoxin toxicity by spironolactone in the mouse

Arch. Intern. Pharmacodyn.

Excretion of 3H-digitoxin and its metabolites following spironolactone pretreatment in rats

Drug Metab. Dis.

Tritiated digoxin studies in human subjects

Arch. Intern. Med.

Tritiated digoxin

Circulation

Metabolism of peruvoside in man

European J. Clin. Pharmacol.

Investigation of the effects of methyltestosterone, cortisone and spironolactone on the hepatic microsomal mixed function oxydase system in male and female rats

Biochem. Pharmacol.

Effect of spironolactone on excretion of ³H-digoxin and its metabolites in rats

Excretion of ³H-digitoxin and its metabolites following spironolactone pretreatment in rats