Pharmacokinetics and metabolism of thioridazine during co-administration of tricyclic antidepressants

1 Because of serious side-effects of thioridazine and tricyclic antidepress ants (cardiotoxicity), a possible influence of imipramine and amitriptyline on the pharmacokinetics and metabolism of thioridazine was investigated in a steady state (2-week treatment) in rats. 2 Imipramine and amitriptyline (5 and 10 mg kg(-1) i.p., respectively) elev ated 30 and 20 fold, respectively, the concentration of thioridazine (10mg kg(-1) i.p.) and its metabolites (N-desmethylthioridazine, 2-sulphoxide, 2- sulphone, 5-sulphoxide) in blood plasma. Similar, yet weaker increases in t he thioridazine concentration were found in the brain. Moreover, an elevati on of thioridazine/metabolite ratios was observed. 3 Imipramine and amitriptyline added to control liver microsomes in vitro i nhibited the metabolism of thioridazine via N-demethylation (an increase in K-m), mono-2-sulphoxidation (an increase in K-m and a decrease in V-max) a nd 5-sulphoxidation (mainly a decrease in V-max). Amitriptyline was a more potent inhibitor than imipramine of the thioridazine metabolism 4 The varying concentration ratios of antidepressant/thioridazine in vivo a ppear to be more important to the final result of the pharmacokinetic inter actions than are relative direct inhibitory effects of the antidepressants on thioridazine metabolism observed in vitro. 5 Besides direct inhibition of the thioridazine metabolism, the decreased a ctivity of cytochrome P450 towards 5-sulphoxidation, produced by chronic jo int administration of thioridazine and the antidepressants, seems to be rel evant to the observed in vivo interaction. 6 The obtained results may also point to inhibition of another, not yet inv estigated, metabolic pathway of thioridazine, which may be inferred from th e simultaneous elevation of concentrations of both thioridazine and the mea sured metabolites.