Summary
The influence of pretreatment with spironolactone (84 mg/kg at 3 days, twice per day) on the tritium levels in plasma, urine and feces of female SD-rats (n=9) was investigated at various time periods after oral administration of 25 μg/kg 3H-digitoxin. In plasma, the concentrations of total radioactivity are reduced in pretreated animals to about 20% of tritium levels in control rats, while the half-life of radioactivity in both groups is almost identical, 2.9 days in pretreated rats and 2.8 days in controls. The lower plasma levels of tritium in pretreated rats coincide with a six-fold decrease in the urinary 3H-elimination and a corresponding increase in the fecal excretion. This is due to a higher biliary clearance of tritiated products in the early phase of elimination. The separation of the excretion products by TLC shows that spironolactone pretreatment enhances the splitting of the glycosidic bonds of digitoxin. The amount of digitoxigenin-bis-digitoxoside and of digitoxigenin-mono-digitoxoside excreted in urine and feces within 96 hrs is four and ten times greater than that recovered in control animals, respectively. The formation of the hydroxylation products digoxin and digoxigenin-bis-digitoxoside is decreased from 50% of the total excreted radioactivity in control to 15% in pretreated rats. The conjugation reactions with glucuronic and sulfuric acid are increased after pretreatment with spironolactone. Thus, the effect of spironolactone on digitoxin kinetics is apparently related to an enhancement of the hepatic excretory mechanism as well as to an enhanced metabolism.
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Abshagen, U.: Effects of pretreatment with spironolactone on pharmacokinetcis of 4‴-methyldigoxin in rats. Naunyn-Schmiedeberg's Arch. Pharmacol. 278, 91–100 (1973)
Castle, M. C., Lage, G. L.: Effect of pretreatment with spironolactone, phenobarbital or β-diethylaminoethyl diphenylpropylacetate (SKF 525-A) on tritium levels in blood, heart and liver of rats at various times after administration of (3H) digitoxin. Biochem. Pharmacol. 21, 1449–1455 (1972)
Castle, M. C., Lage, G. L.: Enhanced biliary excretion of digitoxin following spironolactone as it relates to the prevention of digitoxin toxicity. Res. Comm. Chem. Path. Pharmacol. 5, 99–108 (1973a)
Castle, M. C., Lage, G. L.: Excretion of 3H-digitoxin and its metabolites following spironolactone pretreatment in rats. Drug Metab. Disp. 1, 590–598 (1973b)
Castle, M. C., Lage, G. L.: 3H-digitoxin and its metabolites following spironolactone pretreatment of rats. Res. Comm. Chem. Path. Pharmacol. 6, 601–612 (1973c)
Castle, M. C., Lage, G. L.: Cleavage by β-glucuronidase of the water-soluble metabolites of digitoxin excreted in the bile of control and spironolactone-pretreated rats. Toxicol. appl. Pharmacol. 27, 641–647 (1974)
Huffman, D. H., Shoeman, D. W., Pentikäinen, P., Azarnoff, D. L.: The effect of spironolactone on antipyrine metabolism in man. Pharmacology 10, 338–344 (1973)
Klaassen, C. D.: Stimulation of the development of the hepatic excretory mechanism for ouabain in newborn rats with microsomal enzyme inducers. Toxicol. appl. Pharmacol. 29, 146 (1974)
Leber, H. W., Harders, P., Schütterle, G.: Untersuchungen zum Einfluß von Aldactone auf Arzneimittel abbauende Enzyme im endoplasmatischen Reticulum der Leber der Ratte und des Menschen. Verh. dtsch. Ges. inn. Med. 78, 1358–1362 (1972)
Leber, H. W., Rawer, P., Schütterle, G.: Beeinflussung mikrosomaler Enzyme der Rattenleber durch Spironolacton, Etacrynsäure und Furosemid. Klin. Wschr. 49, 116–118 (1971)
Rietbrock, N., Vöhringer, H.-F.: Metabolism and excretion of 3H-digitoxin in the rat. Biochem. Pharmacol. 23, 2567–2575 (1974)
Selye, H., Mécs, I., Savoie, L.: Inhibition of anesthetics and sedative actions by spironolactone. Anesthesiology 31, 261–264 (1969a)
Selye, H., Mécs, I., Tamura, T.: Effect of spironolactone and norbolethone on the toxicity of digitalis compounds in the rat. Brit. J. Pharmacol. 37, 485–488 (1969b)
Solymoss, B., Classen, H. G., Varga, S.: Increased hepatic microsomal activity induced by spironolactone and other steroids. Proc. Soc. exp. Biol. (N.Y.) 132, 940–942 (1969)
Solymoss, B., Tóth, S., Varga, S., Selye, H.: Protection by spironolactone and oxandrolone against chronic digitoxin or indomethacin intoxication. Toxicol. appl. Pharmacol. 18, 586–592 (1971b)
Solymoss, B., Varga, S., Classen, H. G.: Effect of various steroids on microsomal aliphatic hydroxylation and N-dealkylation. Europ. J. Pharmacol. 10, 127–130 (1970)
Solymoss, B., Werringloer, J., Tóth, S.: The influence of pregnenolone-16α-carbonitrile on hepatic mixed-function oxygenases. Steroids 17, 427–433 (1971a)
Solymoss, B., Zsigmond, G.: Enhanced excretion of bilirubin induced by spironolactone and pregnenolone-16α-carbonitrile. Fifth International Congress on Pharmacology, Volunteer Abstracts 1306 (1972)
Stripp, B., Hamrick, M., Zampaglione, N., Gilette, J.: The effect of spironolactone on drug metabolism by hepatic microsomes. J. Pharmacol. exp. Ther. 176, 766–771 (1971)
Vöhringer, H.-F., Rietbrock, N.: Metabolism and excretion of 3H-digitoxin in man. Clin. Pharmacol. Ther. 16, 796–806 (1974)
Watson, E., Tramell, P., Kalman, S. M.: Identification of submicrogram amounts of digoxin, digitoxin, and their metabolic products. Isolation by chromatography and preparation of derivatives for assay bv electron capture detector. J. Chromatogr. 69, 157–163 (1972)
Wirth, K. E., Frölich, J. C.: The influence of spironolactone on the excretion and metabolism of 3H-digoxin in the rat. Naunyn-Schmiedeberg's Arch. Pharmacol. 282, R107 (1974)
Zsigmond, G., Solymoss, B.: Effect of spironolactone, pregnenolone-16α-carbonitrile and cortisol on the metabolism and biliary excretion of sulfobromophthalein and phenol-3,6-dibromophthalein disulfonate in rats. J. Pharmacol. exp. Ther. 183, 499–507 (1972)
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Vöhringer, H.F., Weller, L. & Rietbrock, N. Influence of spironolactone pretreatment on pharmacokinetics and metabolism of digitoxin in rats. Naunyn-Schmiedeberg's Arch. Pharmacol. 287, 129–139 (1975). https://doi.org/10.1007/BF00510445
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DOI: https://doi.org/10.1007/BF00510445