The influence of selective serotonin reuptake inhibitors (SSRIs) on the pharmacokinetics of thioridazine and its metabolites: in vivo and in vitro studies

Due to its psychotropic profile, thioridazine is a neuroleptic suitable for a combination with antidepressants in a number of complex psychiatric illn esses. However, because of its serious side-effects, such a combination wit h selective serotonin reuptake inhibitors (SSRIs) which inhibit cytochrome P-450 may be dangerous. The aim of the present study was to investigate a p ossible impact of SSRIs on the pharmacokinetics and metabolism of thioridaz ine in a steady state in rats. Thioridazine (10 mg/kg) was injected intrape ritoneally, twice a day, for two weeks, alone or jointly with one of the an tidepressants (fluoxetine, fluvoxamine or sertraline). Concentrations of th ioridazine and its main metabolites (2-sulfoxide = mesoridazine; 2-sulfone = sulforidazine; 5-sulfoxide = ring sulfoxide and N-desmethylthioridazine) were assessed in the blood plasma and brain at 30 min, 6 and 12 h after the last dose of the drugs using an HPLC method. Fluoxetine potently increased (up to 13 times!) the concentrations of thioridazine and its metabolites i n the plasma, especially after 6 and 12 h. Moreover, an increase in the sum of concentrations of thioridazine + metabolites and thioridazine/metabolit e ratios was observed. In vitro studies with control liver microsomes, as w ell as with microsomes of rats treated chronically with fluoxetine show tha t the changes in the thioridazine pharmacokinetics may be attributed to the competitive (N-demethylation, K-i = 23 mu M) and mixed inhibition (2- and 5-sulfoxidation, K-i = 60 mu M and 34 mu M, respectively) of thioridazine m etabolism by fluoxetine, and to the adaptive changes produced by chronic ad ministration of fluoxetine, as reflected by inhibition of N-demethylation a nd formation of sulforidazine. Sertraline seemed to have a tendency to decr ease thioridazine concentration in vivo, though in vitro studies showed tha t - like fluoxetine - it competitively or via mixed mechanism inhibited the three metabolic pathways of thioridazine (K-i = 41 mu M, 64 mu M and 47 mu M, respectively). Chronic treatment with sertraline stimulated thioridazin e 2- and 5-sulfoxidation, which may be responsible for the observed tendenc y of sertraline to decrease concentrations of the neuroleptic. In the case of fluvoxamine, a tendency to increase the thioridazine level was observed, which may be connected with the competitive or mixed inhibition of thiorid azine N-demethylation and 2-sulfoxidation by the antidepressant (K-i = 17 m u M and 167 mu M, respectively). Repeated administration of fluvoxamine did not produce any changes in the activity of thioridazine-metabolizing enzym es. In conclusion, of the SSRIs studied, only fluoxetine produces a substantial increase in the thioridazine level in the plasma and brain. In the case of fluvoxamine, a tendency to increase the thioridazine level should be consi dered. Coadministration of thioridazine and sertraline seems to be safe, th ough a tendency to decrease the thioridazine level may be expected.