Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 285, Issue 3, pp 273–292 | Cite as

Pharmacokinetics in the rat of the hallucinogenic alkaloids harmine and harmaline

  • G. Zetler
  • G. Back
  • H. Iven


  1. 1.

    After i. v. injection in rats, harmine and harmaline were distributed in the organism within a few seconds. In spite of the close chemical relationship, both alkaloids revealed significant pharmacokinetic differences.

  2. 2.

    Highest concentrations occurred for harmine in the lung and for harmaline in the kidney. The uptake into brain was for harmaline slower than for harmine. The rate of elimination was in general smaller for harmaline than for harmine.

  3. 3.

    Harmaline was excreted into chymus and urine to a greater extent than harmine.

  4. 4.

    The binding to proteins of rat plasma was 94.5% for harmine and 52% for harmaline. Concentrations of free drug in plasma water were used to assess the binding to various tissues.

  5. 5.

    The extent of tissue binding and the rate of its development were different for both drugs.

  6. 6.

    The duration of tremor and the strength and decline of bradycardia were determined to compare the distribution of the drugs with their effects.

  7. 7.

    The drug concentration (in brain and heart) at the termination of the effect (tremor and bradycadia) was used as a parameter connecting the pharmacokinetic and the pharmacodynamic events.


Key words

Harmine Harmaline Pharmacokinetics Bradycardia Tremor 


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  1. Bosin, T. R., Campaigne, E., Maickel, R. P.: Biochemical pharmacology of benzo (b)thiophene analogs of harmaline and harmine. Life Sci. 11, 685–691 (1972)Google Scholar
  2. Brodie, B. B., Hogben, C. A. M.: Some physico-chemical factors in drug action. J. Pharm. Pharmacol. 9, 345–380 (1957)Google Scholar
  3. Cohen, Y.: Binding of drugs to plasma and tissue proteins. In: International Encyclopedia of Pharmacology and Therapeutics. Section 78, Vol. I, Cohen, Y. (Ed.), Radionuclides in Pharmacology, pp. 241–273, Oxford, New York, Toronto, Sydney, Braunschweig: Pergamon Press, 1971Google Scholar
  4. Dost, F. H.: Grundlagen der Pharmakokinetik, 2. Aufl. Stuttgart: Thieme 1968Google Scholar
  5. Eichelbaum, M., Hengstmann, J. H., Dengler, H. J.: Das Verteilungsmuster des Chlorphentermins bei Ratte, Kaninchen und Schwein. Naunyn-Schmiedeberg's Arch. Pharmak. 267, 446–456 (1970)Google Scholar
  6. Gibaldi, M., Nagashima, R., Levy, G.: Relationship between drug concentration in plasma or serum and amount of drug in the body. J. pharm. Sci. 58, 193–197 (1969)Google Scholar
  7. Gillette, J. R.: Overview of drug-protein binding. Ann. N. Y. Acad. Sci. 226, 6–17 (1973)Google Scholar
  8. Ho, B. T., Estevez, V., Fritchie, G. E., Tansey, L. W., Idänpään-Heikkilä, J., McIsaac, W. M.: Metabolism of harmaline in rats. Biochem. Pharmacol. 20, 1313–1319 (1971)Google Scholar
  9. Hoffer, A., Osmond, H.: The Hallucinogens. New York: Academic Press Inc. 1967Google Scholar
  10. Jähnchen, E., Krieglstein, J., Kunkel, F., Samuelis, W. J., Wollert, U.: Die Bedeutung der Bindung von Pharmaka an Albumin und Erythrocyten eines Perfusionsmediums der isolierten Rattenleber. Naunyn-Schmiedebergs Arch. Pharmak. 269, 67–84 (1971)Google Scholar
  11. Jusko, W. J., Gibaldi, M.: Effects of change in elimination on various parameters of the two-compartment open model. J. pharm. Sci. 61, 1270–1273 (1972)Google Scholar
  12. Jusko, W. J., Lewis, G. P., Dittert, L. W.: Integral coefficients of multi-compartment pharmacokinetic models. Application to chemotherapy. Chemotherapy 17, 109–120 (1972)Google Scholar
  13. Keen, P.: Effect of binding to plasma proteins on the distribution, activity and elimination of drugs. In: Handbuch der experimentellen Pharmakologie. Eichler, O., Farah, A., Herken, H., Welch, A. D. (Eds.), Vol. XXVIII/1: Concepts in Biochemical Pharmacology. Brodie, B. B., Gillette, J. R., Ackerman, H. S. (Eds.), pp. 213–233. Berlin-Heidelberg-New York: Springer 1971Google Scholar
  14. Kolassa, N., Pfleger, K.: Bindung von Hexobendin an Plasmaproteine und Erythrocyten bei Mensch, Hund und Ratte. Arch. int. Pharmacodyn. 203, 46–54 (1973)Google Scholar
  15. Krieglstein, J.: Bestimmungsmethoden, physikochemische Grundlagen und pharmakokinetische Bedeutung der Plasmaproteinbindung von Arzneimitteln. Arzneimittel-Forsch. 23, 1527–1529 (1973a)Google Scholar
  16. Krieglstein, J.: Die Bedeutung der Lipophilie von Arzneimitteln für deren Verteilung im Organismus. Dtsch. med. Wschr. 98, 1509–1510 (1973b)Google Scholar
  17. Krieglstein, J., Kuschinsky, G.: Über die Wechselwirkung von Phenothiazinderivaten mit Rinderserumalbumin. Naunyn-Schmiedebergs Arch. Pharmak. exp. Path. 262, 1–16 (1969)Google Scholar
  18. Krüger-Thiemer, E.: Application of kinetic analysis for calculation of dosage regimens. In: Siegler, P. E., Moyer, J. H. (Eds.): Animal and Clinical Pharmacologic Techniques in Drug Evaluation, Vol. 2, pp. 217–238, Chicago: Year Book Medical Publishers Inc. 1967Google Scholar
  19. Kurz, H.: Die Bedeutung der Lipoidlöslichkeit in der Pharmakologie. Präparat. Pharmaz. 6, 1–12 (1970)Google Scholar
  20. Levy, G.: Kinetics of pharmacologic effects. Clin. Pharmacol. Ther. 7, 362–372 (1966)Google Scholar
  21. 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)Google Scholar
  22. Martin, B. K.: Potential effect of the plasma proteins on drug distribution. Nature (Lond.) 207, 274–276 (1965)Google Scholar
  23. Naranjo, C.: Psychotropic properties of the harmala alkaloids. In: Ethnopharmacologic Search for Psychoactive Drugs. Efron, D. H., Holmstedt, B., Kline, N.S. (Eds.), pp. 385–391. Public Health Service Publication No. 1645, Washington 1967Google Scholar
  24. Oldendorf, W. H.: Blood-brain barrier premeability to drugs. Ann. Rev. Pharmacol. 14, 239–248 (1974)Google Scholar
  25. Oldendorf, W. H., Hyman, S., Braun, L., Oldendorf, S. Z.: Blood-brain barrier: Penetration of morphine, codeine, heroin, and methadone after carotid injection. Science 178, 984–985 (1972)Google Scholar
  26. Raaflaub, J.: Über die Beziehungen zwischen der Lipidlöslichkeit von Pharmaka und ihrem pharmakokinetischen Verhalten. Experientia (Basel) 26, 457–467 (1970)Google Scholar
  27. Riegelman, S., Loo, J. C. K., Rowland, M.: Shortcomings in pharmacokinetic analysis by conceiving the body to exhibit properties of a single compartment. J. pharm. Sci. 57, 117–123 (1968a)Google Scholar
  28. Riegelman, S., Loo, J., Rowland, M.: Concept of a volume of distribution and possible errors in evaluation of this parameter. J. pharm. Sci. 57, 128–133 (1968b)Google Scholar
  29. Riggs, D. S.: The mathematical approach to physiological problems, pp. 146–161. Cambridge-London: M. I. T. Press, 1972Google Scholar
  30. Schultes, R. E.: Hallucinogens of plant origin. Science 163, 245–254 (1969)Google Scholar
  31. Slotkin, T. A., DiStefano, V., Au, W. Y. W.: Blood levels and urinary excretion of harmine and its metabolites in man and rats. J. Pharmacol. exp. Ther. 173, 26–30 (1970)Google Scholar
  32. Strubelt, O., Back, G., Uhl, E., Zetler, G.: Cardiac output, heart rate, and blood pressure as influenced by equi-antiarrhythmic doses of eight antifibrillatory agents. Naunyn-Schmiedebergs Arch. Pharmak. 271, 346–360 (1971)Google Scholar
  33. Villeneuve, A., Sourkes, T. L.: Metabolism of harmaline and harmine in the rat. Rev. canad. Biol. 25, 231–239 (1966)Google Scholar
  34. Wang, L.: Plasma volume, cell volume, total blood volume and F cells factor in the normal and splenectomized Sherman rat. Amer. J. Physiol. 196, 188–192 (1959)Google Scholar
  35. Wassermann, O.: Studies on the pharmacokinetics of bisquaternary ammonium compounds. I. Synthesis, physico-chemical properties and protein-binding of 3H-labelled hexamethonium and of some of its derivatives. Arzneimittel-Forsch. 22, 1993–1995 (1972)Google Scholar
  36. Zaharko, D. S., Dedrick, R. L.: Applications of pharmacokinetics to cancer chemotherapy. In: Pharmacology and the Future of Man. Proc. 5th Int. Congr. Pharmacology, San Francisco 1972, Vol. 3, pp. 316–331. Basel: Karger 1973Google Scholar
  37. Zetler, G.: Indirect cardiac effects of indole, simple indole derivatives, and harmine. Naunyn-Schmiedebergs Arch. Pharmacol. 283, 165–179 (1974)Google Scholar
  38. Zetler, G., Singbartl, G., Schlosser, L.: Cerebral pharmacokinetics of tremor-producing harmala and iboga alkaloids. Pharmacology 7, 237–248 (1972)Google Scholar

Copyright information

© Springer-Verlag 1974

Authors and Affiliations

  • G. Zetler
    • 1
  • G. Back
    • 1
  • H. Iven
    • 1
  1. 1.Institut für Pharmakologie der Medizinischen HochschuleLübeckFederal Republic of Germany

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