Neuropharmacological properties of amitriptyline, nortriptyline and their metabolites

Amitriptyline, nortriptyline and their metabolites, desmethylnortriptyline, cis and trans 10-hydroxyamitriptyline, cis and trans 10-hydroxynortriptyline and amitriptyline-N-oxide, have been tested for inhibitory effect on the uptake of serotonin (rabbit thrombocytes in vitro) and noradrenaline (mouse atria in vitro and mouse heart in vivo), for anticholinergic activity (guinea-pig ileum in vitro) and for antagonism against tetrabenazine induced inactivity as well as apomorphine and 5-hydroxytryptophan potentiating effect in mice. Amitriptyline inhibits serotonin and noradrenaline uptake equally, whereas nortriptyline is a more potent inhibitor of noradrenaline than of serotonin uptake. The metabolites resemble nortriptyline in this respect. The 10-hydroxylated metabolites are equipotent with amitriptyline as regards noradrenaline uptake inhibition. All the metabolites are less anticholinergic than amitriptyline and nortriptyline. The in vitro results are reflected in the in vivo behavioural tests, although some discrepancies are found, probably due to differences in absorption, distribution, metabolism and excretion. The importance of knowledge concerning pharmacological properties of the metabolites in comparison with amitriptyline and nortriptyline for correlating plasma levels of these and their metabolites to clinical outcome is discussed.