Influence of neuroleptics on the metabolism of tricyclic antidepressants--in vitro experiments with rat liver microsomes

Abstract

The influence of two neuroleptics--the phenothiazine perazine and the butyrophenone haloperidol--on the metabolism of the tricyclic antidepressants amitriptyline (AMI), imipramine (IMI), and chlorimipramine (CMI) was studied in vitro in isolated liver microsomes of female Sprague-Dawley rats. The rats were pretreated over 10 days with either NaCl solutions or with 1, 3, and 10 mg/kg haloperidol or 5 and 15 mg/kg perazine, respectively. The microsomal fraction was incubated with various concentrations of antidepressants. The drugs and their metabolites were analyzed by high-performance liquid chromatography (HPLC). Neither pretreatment with haloperidol nor perazine had any significant influence on the demethylation and N-oxidation activity of the microsomes. Benzylic 10-hydroxylation of AMI or IMI or 10- and 11-hydroxylation of CMI was inhibited significantly by pretreatment with perazine, as was 2-hydroxylation of IMI and CMI, whereas 8-hydroxylation of CMI was not influenced. The inhibition was dose dependent. With haloperidol, only the high dose of 10 mg/kg caused a significant inhibition of benzylic 10-hydroxylation, whereas phenolic hydroxylation was not influenced. The inhibition was much lower than for perazine. Comparing the results with pharmacokinetic studies in humans revealed a good agreement in metabolic pathways. The study could therefore be important in the choice of neuroleptic drugs in combination therapy.