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β-Methyl-digoxin

V. Protein binding, tissue distribution and extra-cardiac effects in rats and mice

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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.

  1. 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.

  2. 2.

    In rats, the DC between skeletal muscle and plasma water decreased in the order digitoxin > digoxin ≫ β-methyl-digoxin.

  3. 3.

    In mice and rats, the DC between brain and plasma water decreased in the order digitoxin ≫ β-methyl-digoxin > digoxin.

  4. 4.

    Protein binding decreased in the order digitoxin ≫ digoxin > β-methyldigoxin.

  5. 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.

  6. 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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Authors and Affiliations

  1. Abteilungen für Medizinische und Chemische Forschung, Boehringer Mannheim GmbH, Mannheim, Germany

    Androniki Roesch, K. Koch & W. Schaumann

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  1. Androniki Roesch
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  2. K. Koch
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  3. W. Schaumann
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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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