HYDROXYLATED METABOLITES OF TRICYCLIC ANTI-DEPRESSANTS - PRE-CLINICAL ASSESSMENT OF ACTIVITY

Abstract

Studies investigating a possible relationship between the plasma concentration of tricyclic antidepressants and clinical response have measured only the tertiary and secondary amine forms of the drugs. Hydroxy metabolites of tricyclic antidepressants might also be active. Hydroxylated imipramine, desipramine, chlorimipramine and nortriptyline inhibit the uptake of norepinephrine and serotonin into synaptosomes to the same extent as the parent compounds in rats and mice. Hydroxylated nortriptyline and imipramine reverse or prevent reserpine-induced motor retardation and ptosis. After chronic imipramine, significant steady-state concentrations of unconjugated hydroxylated metabolites are present in rat tissues including the CSF. Accounting for steady-state concentrations of hydroxylated metabolites of tricyclic antidepressants in man may help clarify whether there is a relationship between active drug concentration and clinical effect.