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Phenobarbital-digitoxin interaction in the Guinea pig liver

  • M. L. Carvalhas
  • M. A. Figueira
  • M. R. Maya
Article
  • 6 Downloads

Summary

The influence of phenobarbital pretreatment on liver concentration of digitoxin and its metabolites was studied in guineapigs after i.p. administration of the cardiac glycoside. During the first hour an increase in liver uptake was observed in pretreated animals. The differences detected in the hepatic subcellular distribution do not seem to explain the higher concentrations found in the liver of phenobarbital pretreated animals. About 80% of the liver radioactivity was found in the supernatants. Inhibition of digitoxin biotransformation by phenobarbital was demonstrated by chromatographic analysis of the organic soluble compounds present in the supernatants. The possible binding of digitoxin and its metabolites to soluble proteins of liver cytosol was excluded by thin-layer gel filtration. The decrease in digitoxin biotransformation seems to be the reason for the increase in liver uptake and for the decrease in bile concentrations, observed in phenobarbital pretreated animals.

Key words

Phenobarbital digitoxin liver subcellular distribution metabolism 

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References

  1. 1.
    Carvalhas, M.L. and Figueira, M.A. (1979): Arch. int. Pharmacodyn. Effect of phenobarbital pretreatment on digitoxin toxicity and biotransformation in guineapigs,242, 35–43.PubMedGoogle Scholar
  2. 2.
    Castle, M.C. and Lage, G.L. (1972): Biochem. Pharmacol. Effect of pretreatment with spironolactone, phenobarbital or β-diethyl-aminoethyl diphenylpropyl acetate (SKF 525-A) on tritium levels in blood, heart and liver of rats at various times after administration of3H digitoxin,21, 1449–1455.CrossRefPubMedGoogle Scholar
  3. 3.
    Conney, A.H. (1967): Pharmacol. Rev. Pharmacological implications of microsomal enzyme induction,19, 317–366.PubMedGoogle Scholar
  4. 4.
    Marzo, A., Ghirardi, P., Preti, A., Lombardo, A., Longhini, C. and Musacci, G. (1977): Biochem. Pharmaced. Subcellular distribution of deslanatoside C, ouabain and digitoxin in the heart and liver of conscious guinea-pigs,26, 2427–2431.CrossRefGoogle Scholar
  5. 5.
    Litwack, G., Ketterer, B. and Arias, I.M. (1971): Nature. Ligandin: a hepatic protein which binds steroids, bilirubin, carcinogens and a number of exogenous organic anions,234, 466–467.CrossRefPubMedGoogle Scholar
  6. 6.
    Reyes, H., Levi, A.J., Gatmaitan, Z. and Arias, I.M. (1969): Proc. natn.Acad.Sci. U.S.A. Organic anion-binding protein in rat liver: drung induction and its physiologic consequence,64, 168–170.CrossRefGoogle Scholar
  7. 7.
    Wolkoff, A.W., Goresky, C.A., Sellin, J., Gatmaitan, Z. and Arias, I.M. (1979): Am. J. Physiol. Role of ligandin in transfer of bilirubin from plasma into liver,236, E638-E648.PubMedGoogle Scholar
  8. 8.
    Cardoso, M.T. and Carvalhas, M.L. (1980): Xenobiotica. Effects of phenobarbital on digitoxin metabolism in guinea-pig liver slices,10, 779–784.CrossRefPubMedGoogle Scholar
  9. 9.
    Klompe, M. (1978): Pharm. Weebl. The role of cytochrome P 450 in the biotransformation of digitoxin and its aglicone. A study with isolated guinea-pig hepatocytes,113, 127–129.Google Scholar
  10. 10.
    Hazato, T., Murayama, A., Matsuzawa, A. and Yamamoto, T. (1979): Anal. Biochem. A new assay of estrogen receptor by thin-layer gel filtration,94, 29–35.CrossRefPubMedGoogle Scholar
  11. 11.
    Lowry, O.H., Rosebrough, N.J. Farr, A.L. and Randall, R.J. (1951): J. Biol. Chem. Protein measurement with the Folin phenol reagent,193, 265–275.PubMedGoogle Scholar
  12. 12.
    Carvalhas, M.L. and Figueira, M.A. (1973): J. Chromatgr. Comparative study of thin-layer chromato-graphic techniques for separation of digoxin, digitoxin and their main metabolites,86, 254–260.CrossRefGoogle Scholar
  13. 13.
    Radola, B.J. (1968): J. Chromatogr. Thin-layer gel filtration of proteins,38, 61–77.CrossRefPubMedGoogle Scholar
  14. 14.
    Davies, R.G. (1971): Computer programing in quantitative biology. Academic Press, London, 97–104.Google Scholar
  15. 15.
    Klaassen, C.D. (1974): J. Pharmacol. exp. Ther. Effect of microsomal enzyme inducers on the biliary excretion of cardiac glycosides,191, 201–211.PubMedGoogle Scholar
  16. 16.
    Yates, M.S., Hiley, C.R., Challiner, M.R. and Park, B.K. (1979): Biochem. Pharmacol. Phenobarbitone effects on hepatic microsomal enzymes and liver blood flow in the guinea-pig,28, 2856–2857.CrossRefPubMedGoogle Scholar
  17. 17.
    Williams, R.T., Millburn, P. and Smith, R.L. (1965): Ann. N.Y. Acad. Sci. The influence of enterohepatic circulation on toxicity of drugs,123, 110–124.CrossRefPubMedGoogle Scholar
  18. 18.
    Levine, W.G. and Singe, R.W. (1972): J. Pharmacol. exp. Ther. Hepatic intracellular distribution of foreign compounds in relation to their biliary excretion,183, 411–419.PubMedGoogle Scholar
  19. 19.
    Spratt, J.L. and Okita, G.T. (1958): Biochem. Pharmacol. Subcellular localization of radioactivity digitoxin,124, 115–119.Google Scholar
  20. 20.
    Levine, W.G. (1972): J. Pharmacol. exp. Ther. Biliary excretion of 3-methylcolanthrene as controlled by its metabolism,183, 420–426.PubMedGoogle Scholar
  21. 21.
    Spratt, J.L. and Okita, G.T. (1958): Biochem. Pharmacol. Protein binding of radioactive digitoxin,124, 109–114.Google Scholar
  22. 22.
    Lukas, D.S. and De Martino, A.G. (1969): J. Clin. Invest. Binding of digitoxin and some related cardenolides to human plasma proteins,48, 1041–1053.CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 1982

Authors and Affiliations

  • M. L. Carvalhas
    • 1
  • M. A. Figueira
    • 1
  • M. R. Maya
    • 1
  1. 1.Biological CenterGulbenkian Institute of ScienceOeirasPortugal

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