Summary
-
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.
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.
Harmaline was excreted into chymus and urine to a greater extent than harmine.
-
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.
The extent of tissue binding and the rate of its development were different for both drugs.
-
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.
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.
Similar content being viewed by others
References
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)
Brodie, B. B., Hogben, C. A. M.: Some physico-chemical factors in drug action. J. Pharm. Pharmacol. 9, 345–380 (1957)
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, 1971
Dost, F. H.: Grundlagen der Pharmakokinetik, 2. Aufl. Stuttgart: Thieme 1968
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)
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)
Gillette, J. R.: Overview of drug-protein binding. Ann. N. Y. Acad. Sci. 226, 6–17 (1973)
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)
Hoffer, A., Osmond, H.: The Hallucinogens. New York: Academic Press Inc. 1967
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)
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)
Jusko, W. J., Lewis, G. P., Dittert, L. W.: Integral coefficients of multi-compartment pharmacokinetic models. Application to chemotherapy. Chemotherapy 17, 109–120 (1972)
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 1971
Kolassa, N., Pfleger, K.: Bindung von Hexobendin an Plasmaproteine und Erythrocyten bei Mensch, Hund und Ratte. Arch. int. Pharmacodyn. 203, 46–54 (1973)
Krieglstein, J.: Bestimmungsmethoden, physikochemische Grundlagen und pharmakokinetische Bedeutung der Plasmaproteinbindung von Arzneimitteln. Arzneimittel-Forsch. 23, 1527–1529 (1973a)
Krieglstein, J.: Die Bedeutung der Lipophilie von Arzneimitteln für deren Verteilung im Organismus. Dtsch. med. Wschr. 98, 1509–1510 (1973b)
Krieglstein, J., Kuschinsky, G.: Über die Wechselwirkung von Phenothiazinderivaten mit Rinderserumalbumin. Naunyn-Schmiedebergs Arch. Pharmak. exp. Path. 262, 1–16 (1969)
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. 1967
Kurz, H.: Die Bedeutung der Lipoidlöslichkeit in der Pharmakologie. Präparat. Pharmaz. 6, 1–12 (1970)
Levy, G.: Kinetics of pharmacologic effects. Clin. Pharmacol. Ther. 7, 362–372 (1966)
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)
Martin, B. K.: Potential effect of the plasma proteins on drug distribution. Nature (Lond.) 207, 274–276 (1965)
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 1967
Oldendorf, W. H.: Blood-brain barrier premeability to drugs. Ann. Rev. Pharmacol. 14, 239–248 (1974)
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)
Raaflaub, J.: Über die Beziehungen zwischen der Lipidlöslichkeit von Pharmaka und ihrem pharmakokinetischen Verhalten. Experientia (Basel) 26, 457–467 (1970)
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)
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)
Riggs, D. S.: The mathematical approach to physiological problems, pp. 146–161. Cambridge-London: M. I. T. Press, 1972
Schultes, R. E.: Hallucinogens of plant origin. Science 163, 245–254 (1969)
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)
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)
Villeneuve, A., Sourkes, T. L.: Metabolism of harmaline and harmine in the rat. Rev. canad. Biol. 25, 231–239 (1966)
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)
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)
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 1973
Zetler, G.: Indirect cardiac effects of indole, simple indole derivatives, and harmine. Naunyn-Schmiedebergs Arch. Pharmacol. 283, 165–179 (1974)
Zetler, G., Singbartl, G., Schlosser, L.: Cerebral pharmacokinetics of tremor-producing harmala and iboga alkaloids. Pharmacology 7, 237–248 (1972)
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Zetler, G., Back, G. & Iven, H. Pharmacokinetics in the rat of the hallucinogenic alkaloids harmine and harmaline. Naunyn-Schmiedeberg's Arch. Pharmacol. 285, 273–292 (1974). https://doi.org/10.1007/BF00498996
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00498996