Inhibition of 5-hydroxytryptamine and noradrenaline uptake in platelets and synaptosomes incubated in plasma from human subjects treated with amitryptyline or nortriptyline: utilization of the principle for a bioassay method.

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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.