Summary
Rats and mice were injected with 3H-labelled β-methyldigoxin, digoxin or digitoxin i.p. Four hours later, the concentrations of radioactivity were measured in the plasma and in skeletal muscle or in the brain. Protein binding in the plasma was determined and the concentration of radioactivity in the plasma water was calculated. By dividing the injected dose or the concentration in the tissue by that in the plasma water, distribution coefficients (DCs) were calculated for the whole body, skeletal muscle and brain. Some extra-cardiac effects of the three glycosides were quantified and the concentrations that may be expected in plasma water, skeletal muscle and brain after the administration of equiactive doses were calculated.
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1.
The DC of the injected dose was lower for β-methyl-digoxin than for digoxin and digitoxin. This difference cannot be explained by a slow elimination of β-methyl-digoxin suggesting that it has a low distribution volume in these species.
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2.
In rats, the DC between skeletal muscle and plasma water decreased in the order digitoxin > digoxin ≫ β-methyl-digoxin.
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3.
In mice and rats, the DC between brain and plasma water decreased in the order digitoxin ≫ β-methyl-digoxin > digoxin.
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4.
Protein binding decreased in the order digitoxin ≫ digoxin > β-methyldigoxin.
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5.
In rats, the doses producing an equal increase in potassium excretion decreased in the order digitoxin > digoxin > β-methyl-digoxin. On the other hand, the concentrations of radioactivity in the plasma water correlated with these doses decreased in the order β-methyl-digoxin > digitoxin ≫ digoxin. There was no significant difference between the intracellular concentrations of digoxin and β-methyl-digoxin in skeletal muscle.
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6.
In mice, there was no clear correlation between inhibition of spontaneous motility or righting reflexes on the rotating rod and the concentrations of radioactivity in the plasma water or in the brain.
β-Methyl-digoxin is moee lipophilic than digoxin but it penetrates less into skeletal muscle. It is as lipophilic as digitoxin, but it penetrates less into the brain of rats and mice. This shows that penetration of the cell membrane by cardiac glycosides does not solely depend on lipid solubility.
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References
Abshagen, U., Kewitz, H., Rietbrock, N.: Distribution of digoxin, digitoxin and ouabain between plasma and erythrocytes in various species. Naunyn-Schmiedebergs Arch. Pharmak. 270, 105–116 (1971)
Bentley, J. D., Burnett, G. H., Conklin, R. L., Wasserburger, R. H.: Clinical application of serum digitoxin levels. Circulation 41, 67–75 (1970)
Bergmann, v., K., Abshagen, U., Rietbrock, N.: Quantitative analysis of digoxin, 4‴-acetyldigoxin and 4‴-methyldigoxin and their metabolites in bile and urine of rats. Naunyn-Schmiedeberg's Arch. Pharmacol. 273, 154–167 (1972)
Damm, K. H., Braun, W., Heckert, H.: Die Wirkung von Probenecid auf die Verteilung von Digitoxin, Digoxin and Ouabain an der Maus. Naunyn-Schmiedeberg's Arch. Pharmacol. 277, 267–279 (1973)
Dengler, H. J., Bodem, G., Wirth, K.: Pharmakokinetische Untersuchungen mit 3H-Digoxin und 3H-Lanatosid beim Menschen. Arzneimittel-Forsch. 23, 64–74 (1973)
Doherty, J. E.: The clinical pharmacology of digitalis glycosides: A review. Amer. J. med. Sci. 255, 382–414 (1968)
Dulce, H. J., Günther, T.: Steuerung des cellulären Elektrolyt- und Wassergehaltes durch Hormone. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 238, 368–390 (1960)
Dutta, S., Marks, B. H.: Species and ionic influences on the accumulation of digitalis glycosides by isolated perfused hearts. Brit. J. Pharmacol. 46, 401–408 (1972)
Gaitondé, B. B., McCarthy, L. E., Borison, H. L.: Central emetic action and toxic effects of digitalis in cats. J. Pharmacol. exp. Ther. 147, 409–415 (1965)
Godfraind, T., Lesne, M.: The uptake of cardiac glycosides in relation to their actions in isolated cardiac muscle. Brit. J. Pharmacol. 46, 488–497 (1972)
Greeff, K.: Tierexperimentelle Untersuchungen über den Einfluß herzwirksamer Glycoside auf den Natrium- and Kaliumhaushalt. Verh. dtsch. Ges. Kreisl.-Forsch. 22, Tagg., 312–318 (1956)
Greeff, K.: Vergleich der kaliuretischen Wirkung verschiedener Glykoside des Strophanthidins und Digitoxigenins bei parenteraler und enteraler Applikation. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 233, 468–483 (1958)
Greeff, K., Kasperat, H.: Vergleich der neurotoxischen Wirkung von Digitalis-glykosiden und Geninen bei intracerebraler und intravenöser Injektion an Mäusen, Ratten und Meerschweinchen. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 242, 76–89 (1961)
Greeff, K., Westermann, E.: Untersuchungen über die muskellähmende Wirkung des Strophanthins. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 226, 103–113 (1955)
Grobecker, H., Piechowski, U., Greeff, K.: Die Wirkung des k-Strophanthins und Digitonins auf den Ionentransport und die Membran-ATPase der Erythrocyten von Menschen, Meerschweinchen und Ratten. Med. exp. (Basel) 9, 273–282 (1963)
Haberland, G., Maerten, G.: Spezifischer Deuterium-und Tritium-Austausch in Cardenoliden and Cardenolidglykosiden. Naturwissenschaften 56, 516 (1969)
Kobinger, W., Wenzel, B., Klupp, H.: Beziehungen zwischen Herzwirkung, toxischer Wirkung und Plasmabindung bei Herzglykosiden. Arneimittel-Forsch. 20, 1862–1865 (1970)
Kramer, P., Horenkamp, J., Willms, B., Scheler, F.: Das Kumulationsverhalten verschiedener Herzglykoside bei Anurie. Dtsch. med. Wschr. 95, 444–453 (1970)
Kumagai, L. F., Catmull, E.: Metabolism of H3-digitoxin in varying thyroidal states. Clin. Res. 18, 186 (1970)
Kuschinsky, K.: Bestimmung der Eiweißbindung verschiedener Herzglykoside mittels Sephadex®-Gelfiltration. Naunyn-Schmiedebergs Arch. Pharmak. exp. Path. 259, 394–399 (1968)
Kuschinsky, K.: über die Bindungseigenschaften von Plasmaproteinen für Herzglykoside. Naunyn-Schmiedebergs Arch. Pharmak. exp. Path. 262, 388–398 (1969)
Kuschinsky, K.: Lüllmann, H., Van Zwieten, P. A.: A comparison of the accumulation and release of H3-ouabain and H3-digitoxin by guinea-pig heart muscle. Brit. J. Pharmacol. 32, 598–608 (1968)
Lendle, L., Mercker, H.: Extracardiale Digitaliswirkungen. Ergebn. Physiol. 51, 200–298 (1961)
Lendle, L., Oldenburg, D.: Prüfung extrakardialer Wirkungen an der digitalis-unterempfindlichen Ratte. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 211, 243–263 (1950)
Levin, V. A., Fenstermacher, J. D., Patlak, C. S.: Sucrose and insulin space measurements of cerebral cortex in four mammalian species. Amer. J. Physiol. 219, 1528–1533 (1970)
Löhr, E., Makoski, H.-Br., Göbbeler, Th., Strötges, M. W.: Beitrag zu der Membran-Permeabilität von Cardiaca (g-Strophanthin, Digoxin and Oxyfedrin) auf Grund von Mikro-Autoradiographien am Meerschweinchenherzen. Arzneimittel-Forsch. 21, 921–927 (1971)
Losert, W., Senft, C., Senft, G.: Extrarenale Wirkungen des Aldosterons und der Spirolactone. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 248, 450–463 (1964)
Lukas, D. S., De Martino, A. G.: Binding of digitoxin and some related cardenolides to human plasma proteins. J. clin. Invest. 48, 1041–1053 (1969)
Lüllmann, H., Peters, T., van Zwieten, P. A.: The distribution of 3H-labelled cardenolides between isolated guinea-pig atrial tissue and circulating, oxygenated whole blood. Brit. J. Pharmacol. 36, 276–285 (1969)
Lyon, A. F., DeGraff, A. C.: The neurotoxic effects of digitalis. Amer. Heart J. 65, 839–840 (1963)
McLennan, H.: The diffusion of potassium, inulin and thiocyanate in the extracellular spaces of mammalian muscle. Biochim. biophys. Acta (Amst.) 21, 472–481 (1956)
Morrison, A. B.: The distribution of intravenously injected inulin in the fluids of the nervous system of the dog and rat. J. clin. Invest. 38, 1769–1777 (1959)
Oliver, G. C., Jr., Parker, B. M., Brasfield, D. L., Parker, C. W.: The measurement of digitoxin in human serum by radioimmunoassay. J. clin. Invest. 47, 1035–1042 (1968)
Patel, N. K., Foss, N. E.: Interaction of some pharmaceuticals with macromolecules J. pharm. Sci. 53, 94–97 (1964)
Rasmussen, K., Jervell, J., Storstein, L., Gjerdrum, K.: Digitoxin kinetics in patients with impaired renal function. Clin. Pharm. Ther. 13, 6–14 (1972)
Reiter, M.: Die Wertbestimmung inotrop wirkender Arzneimittel am isolierten Papillarmuskel. Arzneimittel-Forsch. 17, 1249–1253 (1967)
Repke, K.: Verteilung, Ausscheidung und Stoffwechsel von Digitoxin bei der Ratte. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 233, 271–283 (1958)
Repke, K.: Über Spaltung und Hydroxylierung von Digitoxin bei der Ratte. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 237, 34–48 (1959)
Rietbrock, N., Abshagen, U., v. Bergmann, K., Kewitz, H.: Pharmacokinetics of digoxin and its 4‴-acetyl- and methylderivates in the rat. Naunyn-Schmiedeber's Arch. Pharmacol. 274, 171–181 (1972)
Schaumann, W.: Die Pharmakokinetic von Digitalis-Glykosiden und ihre Bedeutung für die Therapie. Therapiewoche (in print)
Schaumann, W., Stoepel, K.: Zur quantitativen Beurteilung von zentraler Erregung und Dämpfung im Tierversuch. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 241, 383–392 (1961)
Sisson, W. B., Oldendorf, W. H.: Brain distribution spaces of mannitol-3H, inulin-14C, and dextran-14C in the rat. Amer. J. Physiol. 221, 214–217 (1971)
Smith, T. W., Haber, E.: Digoxin intoxication: The relationship of clinical presentation to serum digoxin concentration. J. clin. Invest. 49, 2377 (1970)
Strobach, H., Greeff, K., Horster, F. A., Wildmeister, W.: Radioimmunologische Glykosidbestimmungen nach Gabe von Digoxin und Digoxinderivaten beim Menschen. Naunyn-Schmiedeberg's Arch. Pharmacol. 274, R 113 (1972)
Wartburg, A., v., Kalberer, F., Rutschmann, J.: Tritium-labelled cardiac glycosides: digoxin-[12α-3H]. Biochem. Pharmacol. 14, 1883–1889 (1965)
Werbin, H., Chaikoff, I. L., Imada, M. R.: Rapid sensitive method for determining H3-water in body fluids by liquid scintillation spectrometry. Proc. Soc. exp. Biol. (N. Y.) 102, 8–12 (1959)
Wirth, K., Bodem, G., Dengler, H. J.: Resorption, Ausscheidung und Stoffwechsel von Digoxin und digoxinverwandten Verbindungen. In: Aktuelle Digitalis-probleme. Pharmakokinetik. Digitalis bei Herzinfarkt, S. 51–61. Berliner Arbeitstagung Dez. 1970. München: Urban & Schwarzenberg 1972
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Roesch, A., Koch, K. & Schaumann, W. β-Methyl-digoxin. Naunyn-Schmiedeberg's Arch. Pharmacol. 279, 211–226 (1973). https://doi.org/10.1007/BF00500601
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DOI: https://doi.org/10.1007/BF00500601