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European Journal of Clinical Pharmacology

, Volume 10, Issue 2, pp 101–108 | Cite as

Pharmacokinetics and pharmacodynamics of methyl proscillaridin in healthy man

  • G. G. Belz
  • H. Schreiter
  • G. K. Wolf
Originals

Summary

The aim of this study was to obtain data about the pharmacological properties of a new glycoside derivative in man. Plasma concentrations and ECG parameters were measured after oral and intravenous administration of a single dose of 1.2 mg methyl proscillaridin in 16 healthy volunteers, using a strictly randomized, two-period change-over design. Glycoside concentrations were measured using a modified86Rb-erythrocyte-assay. QT-duration, corrected for frequency (QTc), was the principal variable measured in the ECG. By either route, there was a maximum plasma level after 1 hour, which had decreased to a minimum at 3 hours, followed by a second peak at 4 to 10 hours (orally>iv). From 10 to 72 hours the concentrations decreased with a median t 1/2 of 23.3 hours (iv) and 33.0 hours (orally). Comparison of the ratio of plasma concentrations following oral and iv administration resulted in a bioavailability of 69 % using the 48 hour plasma levels, and 59 % using the areas under the concentration-time curves. The mean QTc was maximally shortened to 28 msec at 1 hour after iv and to 19 msec at 10 hours after the oral dose. A distinct similarity between time-concentration and time-QTc curves was seen after the initial distribution phase, both after oral and intravenous administration. The new derivative shows a rapid elimination. Its bioavailability is reasonably high.

Key words

Cardiac glycosides methyl proscillaridin plasma concentrations electrocardiogram bioavailability 86Rb-erythrocyte assay 

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References

  1. 1.
    Apter, L., Ashman, R., Hull, E.: A quantitative study on the effects of ouabain upon the electrocardiogram. J. Pharmacol. exp. Ther.82, 227 -238 (1944)Google Scholar
  2. 2.
    Belz, G.G.: Klinisch-experimentelle Untersuchungen mit dem Herzglykosid Proscillaridin unter besonderer Berücksichtigung seiner enteralen Resorptionsquote. Med. Klin.63, 96- 102 (1968)Google Scholar
  3. 3.
    Belz, G.G., Vollmer, K.O., Wissler, J.H.: Zur Hemmwirkung von Herzglykosiden auf die86Rb-Aufnahme der Erythrozyten: I. Methodische Untersuchungen zur Konzentrations-bestimmung von Cymarin und Digitoxin. Europ. J. clin. Pharmacol.4, 92 - 98 (1972)Google Scholar
  4. 4.
    Belz, G.G., Stauch, M., Belz, G., Kurbjuweit, H.G., Oberdorf, A.: The effect of various cardenolides and bufadienolides on the86Rbuptake of human erythrocytes. Naunyn-Schmiedeberg's Arch. Pharmacol.280, 353 - 362 (1973)Google Scholar
  5. 5.
    Belz, G.G., Stauch, M., Rudofsky, G.: Plasma levels of proscillaridin after oral administration of a single dose. Europ. J. clin. Pharmacol.7, 95 - 97 (1974)Google Scholar
  6. 6.
    Belz, G.G., Bader, H.: Effect of oral charcoal on plasma levels of intravenous methyl proscillaridin. Klin. Wschr.52, 1134 - 1135 (1974)Google Scholar
  7. 7.
    Belz, G.G., Staudt, R., Nübling, H., Rietbrock, N.: Pharmacokinetics and metabolism of repetitive methyl proscillaridin administration in man. Naunyn-Schmiedeberg's Arch. Pharmacol.285, R4 (1974)Google Scholar
  8. 8.
    Belz, G.G., Brech, W.J.: Plasmaspiegel und Kumulationsverhalten von Proscillaridin bei Niereninsuffizienz. Klin. Wschr.52, 640 - 644 (1974)Google Scholar
  9. 9.
    Belz, G.G., Nübling, H., Schmidt-Wiederkehr, P., Franz, H.E.: Plasmakonzentrationen und Elimination von Methylproscillaridin bei Niereninsuffizienz. Klin. Wschr.52, 1078 - 1081 (1974)Google Scholar
  10. 10.
    Belz, G.G., Rudofsky, G., Lossnitzer, K., Wolf, G., Stauch, M.: Plasmaspiegel und Elektrokardiogramm nach intravenöser Applikation von Proscillaridin und Digoxin. Z. Kardiologie63, 201 - 211 (1974)Google Scholar
  11. 11.
    Belz, G.G., Schreiter, H.: Influence of plasma on the glycoside induced inhibition of86Rb-uptake of human erythrocytes. Z. Kardiologie63, 475 - 479 (1974)Google Scholar
  12. 12.
    Garett, E.R.: Theoretische Pharmakokinetik. In: Klinische Pharmakologie und Pharmakotherapie, (eds. H.P. Kümmerle, E.R. Garett, K.H. Spitzy) 2nd ed. p. 40. München: Urban & Schwarzenberg 1973Google Scholar
  13. 13.
    Gebhardt, W., Reindell, H., Heining, J., Büchner, C., Danner, D., Moser, F., Wöhler, F., Hoffmann, G., Winkelmann, G.: Klinische Erfahrungen mit Talusin (Proscillaridin). Med. Klin.60, 893 - 898 und 964 – 969 (1965)Google Scholar
  14. 14.
    Gould, L., Fisch, S., Cherbakoff, A., DeGraff, A.C.: Clinical studies on proscillaridin, a new squill glycoside. J. clin. Pharmacol.11, 135 - 145 (1971)Google Scholar
  15. 15.
    Greenblatt, D.J., Duhme, D.W., Koch-Weser, J., Smith, T.W.: Evaluation of digoxin bioavailability in single dose studies. New Engl. J. Med.289, 651- 654 (1973)Google Scholar
  16. 16.
    Greenblatt, D.J., Duhme, D.W., Koch-Weser, J., Smith, T.W.: Equivalent bioavailability from digoxin elixir and rapid dissolution tablets. J. Amer. med. Ass.229, 1774 - 1777 (1974)Google Scholar
  17. 17.
    Grizzle, J.E.: The two-period change-over design and its use in clinical trials. Biometrics21, 467 - 480 (1965)Google Scholar
  18. 18.
    Hänel, J., Meiffert, G.: Klinisch-experimentelle Studie zur Charakterisierung eines Herzglykosids. Med. Welt17, 1404 - 1408 (1966)Google Scholar
  19. 19.
    Hegglin, R.: Die Klinik der energetisch-dynamischen Herzinsuffizienz. Basel: S. Karger 1947Google Scholar
  20. 20.
    Ito, M., Hollander, P.B., Marks, B.H., Dutta, S.: The effects of six cardiac glycosides on the transmembrane potential and contractile characteristic of the right ventricle of guinea pigs. J. Pharmacol. exp. Ther.172, 188 - 195 (1972)Google Scholar
  21. 21.
    Kober, G., Kaltenbach, M.: Vergleichende elektrokardiographische Untersuchungen zur Resorption von β-Methyldigoxin. Herz/Kreisl.3, 331 - 334 (1971)Google Scholar
  22. 22.
    Koch, E.G.: The use of nonparametric methods in the statistical analysis of the two-period change-over design. Biometrics28, 577 - 584 (1972)Google Scholar
  23. 23.
    Kubinyi, H.: Proscillaridinmethyläther. Arch. pharm. (Weinheim)304, 531 - 543 (1971)Google Scholar
  24. 24.
    Kurbjuweit, H.G.: Zur Pharmakologie eines neu in die Therapie eingeführten Reinglykosids. Arzneimittel-Forsch.14, 716 - 720 (1964)Google Scholar
  25. 25.
    Larbig, D., Kochsieck, K., Schrader, C.: Klinische Aspekte der radioimmunologischen Bestimmung der Serum-Digoxin-Konzentration. Dtsch. med. Wschr.97, 139- 145 (1972)Google Scholar
  26. 26.
    Lepeschkin, E.: Modern electrocardiography: Vol. I. The P-Q-R-S-T-U-complex. Baltimore: Williams & Williams Company 1951Google Scholar
  27. 27.
    Lienert, G.A.: Verteilungsfreie Methoden in der Biostatistik. 2nd ed., S. 644- 646. Meisenheim am Glan: A. Hain 1973Google Scholar
  28. 28.
    Lowenstein, J.M., Corill, E.M.: An improved method for measuring plasma and tissue levels of digitalis glycosides. J. Lab. clin. Med.67, 1048 - 1052 (1966)Google Scholar
  29. 29.
    Nyberg, L., Andersson, K.E., Bertler, A.: Bioavailability of digoxin from tablets. III. Availability of digoxin in man from preparations with different dissolution rate. Acta pharm. suecica11, 471 - 492 (1974)Google Scholar
  30. 30.
    Schellhorn, W., Kaltenbach, M.: Ekg-Untersuchungen über die Resorptionsquote herzwirkender Glykoside. Med. Klin.64, 832 - 836 (1969)Google Scholar
  31. 31.
    Vollmer, K.O., Wissler, J.H., Belz, G.G.: Zur Hemmwirkung von Herzglykosiden auf die86Rb-Aufnahme der Erythrozyten: II. Spezifität der Hemmwirkung unter besonderer Berücksichtigung der Cymarin-Reihe. Europ. J. clin. Pharmacol.4, 99- 103 (1972)Google Scholar
  32. 32.
    Weissler, A.M., Snyder, J.R., Schoenfeld, C.D., Cohen, S.: Assay of digitalis glycosides in man. Amer. J. Cardiol.17, 768 - 780 (1966)Google Scholar

Copyright information

© Springer-Verlag 1976

Authors and Affiliations

  • G. G. Belz
    • 1
  • H. Schreiter
    • 1
  • G. K. Wolf
    • 2
  1. 1.Abteilung Pharmakologie, Sektion Cardiologie und Angiologie des Zentrums für Innere Medizin und KinderheilkundeUniversität Ulm, Bundeswehrkrankenhaus UlmGermany
  2. 2.Institut für Medizinische DokumentationStatistik und Datenverarbeitung der Universität HeidelbergFederal Republic of Germany

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