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Digitoxin and its metabolites in patients with liver cirrhosis

  • A. Nokhodian
  • S. R. C. J. Santos
  • W. Kirch
Article

Summary

Pharmacokinetic profile and urinary excretion of digitoxin and 4 metabolites were investigated in 9 patients with biopsy confirmed liver cirrhosis (median antipyrine clearance 20.0±5.4 ml/min; X±SEM) and were compared with that of 8 healthy volunteers (antipyrine clearance 36.9±4.9 ml/min) following intravenous and p.o. administration of 1 mg digitoxin. The kinetic parameters derived from the digitoxin plasma concentration time curve and from urinary recovery including total clearance of unchanged digitoxin did not differ significantly between both groups investigated. Renal clearance of digitoxin was 0.017±0.005 ml/min/kg in the patient group and 0.011±0.002 ml/min/kg in the volunteers (NS); it was 0.00340±0.00047 ml/min/kg and 0.00223±0.00039 ml/min/kg, respectively for digitoxigenin-bis-digitoxoside (NS), 0.00006±0.00001 ml/min/kg and 0.00016±0.00005 ml/min/kg for digitoxigenin-mono-digitoxoside (P<0.05), 0.00041±0.00013 ml/min/kg and 0.00088±0.00032 ml/min/kg for digitoxigenin (P<0.05), 0.00135±0.00049 ml/min/kg and 0.00113±0.00042 ml/min/kg for digoxin (NS). In conclusion, hydrolysis of digitoxin is altered in liver cirrhosis, whereby a significant reduction in the renal clearance and urinary recovery of digitoxigenin-mono-digitoxoside and digitoxigenin was seen in the present study.

Keywords

Digitoxin metabolites pharmacokinetics liver cirrhosis HPLC and RIA methods 

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References

  1. 1.
    Lukas D.S., Peterson R.E. (1966): Double isotope dilution derivative assay of digitoxin in plasma urine and stools of patients maintained on the drug. J. Clin. Invest., 45, 782–795.CrossRefPubMedGoogle Scholar
  2. 2.
    Smith T.W. (1970): Radioimmunoassay for serum digitoxin concentrations: Methodology and clinical experience. J. Pharmacol. Exp. Ther., 175, 352–360.PubMedGoogle Scholar
  3. 3.
    Storstein L. (1974): Studies on digitalis. I. Renal excretion of digitoxin and its cardioactive metabolites. Clin. Pharmacol. Ther., 16, 14–24.PubMedGoogle Scholar
  4. 4.
    Storstein L. (1974): Studies on digitalis. II. The influence of renal function on the renal excretion of digitoxin and its cardioactive metabolites. Clin. Pharmacol. Ther., 16, 25–34.PubMedGoogle Scholar
  5. 5.
    Storstein L. (1976): Studies on digitalis. VII. Influence of nefrotic syndrome on protein binding, pharmacokinetics and renal excretion of digitoxin and cardioactive metabolites. Clin. Pharmacol. Ther., 20, 158–166.PubMedGoogle Scholar
  6. 6.
    Storstein L. (1977): Studies on digitalis. XI. Digitoxin metabolism in patients with impaired renal function. Clin. Pharmacol. Ther., 21, 536–546.PubMedGoogle Scholar
  7. 7.
    Gjerdrum K. (1970): Determination of digitalis in blood. Acta. Med. Scand., 187, 371–379.CrossRefPubMedGoogle Scholar
  8. 8.
    Gold H., Cattell M., Modell W., Kwit M.T., Kramer M.L., Zahm W. (1944): Clinical studies on digitoxin (digitaline nativelle) with further observations on its use in the single coverage full dose method of digitalization. J. Pharmacol. Exp. Ther., 82, 187–195.Google Scholar
  9. 9.
    Graves P.E., Fenster P.E., McFarland R.T., Marcus F.I., Perrier D. (1984): Kinetics of digitoxin and the bis- and mono-digitoxosides of digitoxigenin in normal subjects. Clin. Pharmacol. Ther., 36, 601–606.PubMedGoogle Scholar
  10. 10.
    Lukas D.S. (1971): Some aspects of the distribution and disposition of digitoxin in man. Ann. NY Acad. Sci. USA, 179, 338–361.CrossRefGoogle Scholar
  11. 11.
    McFarland R.T., Marcus F.I., Fenster P.E., Graves P.E., Perrier D. (1984): Pharmacokinetics and bioavailability of digitoxin by a specific assay. Eur. J. Clin. Pharmacol., 27, 85–89.Google Scholar
  12. 12.
    Okita G.T., Talso P.J., Curry Jr J.H., Smith Jr F.D., Geiling E.M.K. (1955): Blood level studies of14C-digitoxin in human subjects with cardiac failure. J. Pharmacol. Exp. Ther., 113, 376–382.PubMedGoogle Scholar
  13. 13.
    Oliver G.C., Parker B.M., Brasfield D.L., Parker C.W. (1968): The measurement of digitoxin in human serum by radioimmunoassay. J. Clin. Invest., 47, 1035–1042.PubMedGoogle Scholar
  14. 14.
    Graves P.E., Fenster P.E., McFarland R.T., Marcus F.I., Perrier D. (1984): Kinetics of digitoxin and the bis- and mono-digitoxosides of digitoxigenin in renal insufficiency. Clin. Pharmacol. Ther., 36, 607–612.PubMedGoogle Scholar
  15. 15.
    Storstein L. (1976): Studies on digitalis. V. The influence of impaired renal function, hemodialysis, and drug interaction on serum protein binding of digitoxin and digoxin. Clin. Pharmacol. Ther., 20, 6–14.PubMedGoogle Scholar
  16. 16.
    Vöhringer H.F., Rietbrock N., Spurny P., Kuhlmann J., Hampl H., Baethke R. (1976): Disposition of digitoxin in renal failure. Clin. Pharmacol. Ther., 19, 387–395.PubMedGoogle Scholar
  17. 17.
    Lahrtz H., Reinhold H.M., Van Zwieten P.A. (1969): Serum-Konzentration und Ausscheidung von3H-Digitoxin beim Menschen unter normalen und pathologischen Bedingungen. Klin. Wschr., 47, 695–700.CrossRefPubMedGoogle Scholar
  18. 18.
    Kirch W., Ohnhaus E.E., Dylewicz P., Pabst J., Storstein L. (1986): Bioavailability and elimination of digitoxin in patients with hepatorenal insufficiency. Am. Heart J., 111, 325–329.CrossRefPubMedGoogle Scholar
  19. 19.
    Kirch W., Ohnhaus E.E., Pabst J., Storstein L. (1989): Digitoxin in patients with hepatorenal insufficiency after repeated oral administration. Eur. Heart J., 10, 40–47.PubMedGoogle Scholar
  20. 20.
    Maier C., Kolenda K.D. (1983): Digitoxin bei hepatorenaler Insuffizienz. Dtsch Med. Wschr., 108, 1475–1480.CrossRefPubMedGoogle Scholar
  21. 21.
    Santos S.R.C.J., Ohnhaus E.E., Ketteringham N.R., Kirch W. (1987): Simultaneous analysis of digitoxin and clinically relevant metabolites using HPLC (high performance liquid chromatography) and RIA (radioimmunoassay). J. Chromatogr., 419, 155–164.CrossRefPubMedGoogle Scholar
  22. 22.
    Ohnhaus E.E., Kirchhof B., Penheim E. (1979): Effect of enzyme induction on plasma lipids using antipyrine, phenobarbital and rifampicin. Clin. Pharmacol. Ther., 25, 591–597.PubMedGoogle Scholar
  23. 23.
    Wagner J.G. (1975): Fundamentals of Clinical Pharmacokinetics. Hamilton, IL, USA, Drug Inter. Publ.Google Scholar
  24. 24.
    Ritschel W.A. (1980): Handbook of Basic Pharmacokinetics 2nd edn. Hamilton, IL, USA, Drug Inter. Publ.Google Scholar
  25. 25.
    Sachs L. (1984): Angewandte Statistik, 6th edn. Berlin, Heidelberg, New York: Springer.Google Scholar
  26. 26.
    Storstein L., Amlie P.J. (1979): Pharmacokinetics and metabolism in patients with chronic and active hepatitis. In: Rietbrock N., Greeff K. eds. Frankfurt, Schattauer (1978), München, Schatauer, (1979), p. 191.Google Scholar
  27. 27.
    Zilly W., Richter E., Rietbrock N. (1975): Pharmacokinetics and metabolism of digoxin and β-methyl-digoxin-12a3H in patients with acute hepatitis. Clin. Pharmacol. Ther., 17, 302–309.PubMedGoogle Scholar
  28. 28.
    Lüllmann H., Peters T. (1971): The cardioactivity of digitoxin metabolites. Eur. J. Pharmacol., 14, 204–205.CrossRefGoogle Scholar
  29. 29.
    Böttcher H., Lüllmann H., Proppe D. (1973): Comparison of digoxin with digitoxin on cat heart lung preparation. Eur. J. Pharmacol., 22, 109–111.CrossRefPubMedGoogle Scholar
  30. 30.
    Vöhringer H.F., Rietbrock N. (1981): Digitalis therapy in renal failure with special regard to digitoxin. Int. J. Clin. Pharmacol. Ther. Toxicol., 4, 174–184.Google Scholar
  31. 31.
    Blaschke T.F. (1977): Protein binding and kinetics of drugs in liver disease. Clin. Pharmacokinet., 2, 32–46.CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • A. Nokhodian
    • 1
  • S. R. C. J. Santos
    • 2
  • W. Kirch
    • 1
  1. 1.I. Medizinische KlinikChristian-Albrechts-UniversitätKiel 1Germany
  2. 2.Advanced Center on Clinical Pharmacology, Research Laboratory, Heart Institute-School of MedicineUniversity of Sao PauloBrazil

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