Abstract
To estimate the inhibition of amine uptake caused in vivo by tricyclic drugs used at a clinical dose, normal human blood platelets or rat hypothalamic or cortical synaptosomes were incubated with 3H-5-hydroxytryptamine (3H-5-HT) or 3H-noradrenaline (3H-NA) in platelet-free plasma of healthy volunteers receiving a single dose of 50 mg amitriptyline (AT) or nortriptyline (NT) orally. Venous blood samples were taken 2–72 h after drug administration. AT and NT were assayed gas-chromatographically. The uptake-inhibiting potency in the plasma samples was measured as a percentage of the uptake in control plasma taken before drug administration. The observed effect was compared with the uptake inhibition caused by known concentrations of the drug added to control plasma in vitro. In most experiments there was a correlation between the gas-chromatographically assayed AT or NT and uptake inhibition. 5-HT uptake in platelets was inhibited by both drugs, and so was NA uptake in rat cortical synaptosomes. 5-HT uptake by hypothalamic synaptosomes, however, was not sensitive enough to reveal the small concentrations of drugs. In platelets a poor correlation was found 12 h post AT administration, since the effect found in the biological assay outlasted the chemically assayed AT and NT. Tricyclic antidepressants are metabolized to a variable degree to both active and inactive metabolites. After AT, its active demethylated metabolite NT did not seem to explain the effect; recently potent 2-hydroxylated metabolites of imipramine have been postulated. It remains to be clarified whether or not such active (as yet unidentified) metabolites of AT and NT contribute to their uptake-inhibiting effects. Neither drug showed any remarkable specificity as to NA or 5-HT uptake.
Similar content being viewed by others
References
Abrams, W. B., Solomon, H. M.: The human platelets as a pharmacologic model for the adrenergic neuron. The uptake and release of norepinephrine. Clin. Pharmacol. Ther. 10, 702–709 (1969)
Borgâ, O., Hamberger, B., Malmfors, T., Sjöqvist, F.: The role of plasma protein binding in the inhibitory effect of nortriptyline on the neuronal uptake of norepinephrine. Clin. Pharmacol. Ther. 11, 581–588 (1970)
Born, G. V. R., Hornykiewicz, O., Stafford, A.: The uptake of adrenaline and noradrenaline by blood platelets of the pig. Br. J. Pharmacol. 13, 411–414 (1958)
Burrows, G., Scoggins, B. A., Turecek, L. R., Davies, B.: Plasma nortriptyline and clinical response. Clin. Pharmacol. Ther. 16, 639–644 (1974)
Coppen, A., Montgomery, S., Chose, K., Rama Rao, V. A., Bailey, J., Christiansen, J., Mikkleson, P. L., van Praag, H. M., van de Poel, F., Minsker, E. J., Kozulja, V. G., Matussek, N., Kungkunz, G., Jørgensen, A.: Amitriptyline plasmaconcentration and clinical effect. Lancet 1978I, 63–66
Crow, T. J.: Biochemical effects of some new antidepressants: Putative mechanisms of antidepressant effect. In: Advances in pharmacology and therapeutics, vol. 5, C. Dumont, ed., pp. 177–185. Oxford: Pergamon 1979
Gordon, J. L., Olverman, H. J.: 5-Hydroxytryptamine and dopamine transport by rat and human blood platelets. Br. J. Pharmacol. 62, 219–226 (1978)
Hamberger, B., Tuck, J. R.: Effect of tricyclic antidepressants on uptake of noradrenaline and 5-hydroxytryptamine into rat brain slices incubated in buffer or human plasma. Eur. J. Clin. Pharmacol. 5, 229–235 (1973)
Hammar, C. G., Alexandersson, B., Holmstedt, B., Sjöqvist, F.: Gaschromatography-mass spectrometry of nortriptyline in body fluids of man. Clin. Pharmacol. Ther. 12, 496–505 (1971)
Javaid, J. I., Perel, J. M., Davis, J. M.: Inhibition of biogenic amines uptake by imipramine, desipramine, 2-OH-imipramine and 2-OH-desipramine in rat brain. Life Sci. 24, 21–28 (1979)
Kruse, H., Hoffman, I., Gerhards, H. J., Level, M., Schacht, U.: Pharmacological and biochemical studies with three metabolites of nomifensine Psychopharmacology 51, 117–123 (1977)
Lahovaara, S., Neuvenen, P., Paasonen, M. K.: Uptake of noradrenaline by human platelets. Scand. J. Clin. Lab. Invest. 25, 18 (1970)
Nakano, S., Hollister, L. E.: No circadian effect on nortriptyline kinetics in man. Clin. Pharmacol. Ther. 23, 199–203 (1978)
Potter, W. Z., Calil, H. M., Manian, A. A., Zavadil, A. P., Goodwin, F. K.: Hydroxylated metabolites of tricyclic antidepressants: Preclinical assesment of activity. Biol. Psychiatry 14, 601–613 (1979)
Tuomisto, J., Tukiainen, E., Ahlfors, U. G.: Decreased uptake of 5-hydroxytryptamine in blood platelets from patients with endogenous depression. Psychopharmacology 65, 141–147 (1979)
Tuomisto, J., Tuomisto, L.: Accumulation of dopamine into striatal synaptosomes and its inhibition: Comparison of crude, partially purified and purified synaptosomal preparations. Med. Biol. 57, 238–245 (1979)
Ziegler, V. E., Fuller, T. A., Biggs, J. T.: Nortriptyline and 10-hydroxynortriptyline plasma concentrations. J. Pharm. Pharmacol. 28, 849–850 (1976)
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Tuomisto, J., Tukiainen, E., Voutilainen, R. et al. Inhibition of 5-hydroxytryptamine and noradrenaline uptake in platelets and synaptosomes incubated in plasma from human subjects treated with amitriptyline or nortriptyline: Utilization of the principle for a bioassay method. Psychopharmacology 69, 137–142 (1980). https://doi.org/10.1007/BF00427639
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF00427639