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

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.

Comparison of the metabolism of the three antidepressants amitriptyline, imipramine, and chlorimipramine in vitro in rat liver microsomes.

The metabolism of the tricyclic antidepressants amitriptyline (AMI), imipramine (IMI), chlorimipramine (CMI) and some of their metabolites was studied in vitro in isolated liver microsomes of female Spraque-Dawley rats. Nine metabolites of AMI, seven metabolites of IMI, and 11 metabolites of CMI were quantitatively determined with high-performance liquid chromatography. The main metabolic reactions, mediated by an NADPH generating system, were hydroxylation, demethylation, and N-oxidation. The ratio of these reactions was different for the three drugs. AMI was hydroxylated more than CMI and CMI more than IMI. The order for demethylation was CMI greater than AMI = IMI, the order for N-oxidation IMI greater than CMI less than or equal to AMI. The substrate dependence of metabolism was investigated. Demethylation and N-oxidation increased proportionally to increasing substrate concentrations, whereas formation of hydroxylated metabolites became saturated (in the concentration range of 10(-6)-10(-5) M). The in vitro metabolism was compared with the in vivo metabolism in humans, reflected by the plasma concentrations of these drugs and their metabolites. A good agreement in metabolic pathways was found.