Promazine pharmacokinetics during concurrent treatment with tricyclic antidepressants

The aim of the present study was to search for a possible effect of tricyclic antidepressants on the pharmacokinetics of promazine. Male Wistar rats received promazine and/or an antidepressant (amitriptyline, imipramine) at a dose of 10 mg/kg i.p. twice a day for two weeks. Amitriptyline increased the plasma concentrations of promazine and N-desmethylpromazine. The concentration of promazine sulfoxide was lowered after 30 min, but later it was raised after 6 and 12 h. The interaction was pronounced after 6 and 12 h when the concentration of promazine was 3 times as high, that of N-desmethylpromazine 25 times as high, and that of sulfoxide 22 times as high as those observed after administration of promazine alone. Similar results were obtained in the brain. Imipramine produced less distinct changes in promazine pharmacokinetics. It did not produce any significant changes in promazine concentration (a tendency to raise it after 30 min was observed) in plasma, but it significantly increased the concentration of N-desmethylpromazine and decreased that of promazine sulfoxide. Changes in the brain did not follow closely those in the plasma. In the brain, significant increases in the levels of promazine and its metabolites were observed after 6 and 12 h. In vitro studies with liver microsomes showed that chronic co-administration of the antidepressants did not significantly influence the rate of promazine demethylation and sulfoxidation. Instead, the Lineweaver-Burk's analysis showed that both amitriptyline and imipramine competitively inhibited the two metabolic pathways of the neuroleptic. The potency of imipramine to inhibit the promazine metabolism in vitro was lower than that of amitriptyline, which was in line with its weaker effect on the pharmacokinetics of promazine in vivo. The observed increase in the sum of concentrations of the measured compounds (promazine + metabolites) in the plasma suggests additional inhibition by amitriptyline of another, metabolic pathway of promazine (e.g. hydroxylation). It is concluded that amitriptyline and imipramine which interfere with the metabolism (and probably distribution) of promazine produce potent increases in the brain (in the case of amitriptyline also in the plasma) concentrations of the neuroleptic.