The effect of selective serotonin reuptake inhibitors (SSRIs) on the pharmacokinetics and metabolism of perazine in the rat

The aim of this study was to investigate the effect of three selective sero tonin reuptake inhibitors (SSRIs), fluoxetine, fluvoxamine and sertraline, on the pharmacokinetics and metabolism of perazine in a steady stale in rat s. Perazine (10 mg kg(-1), i.p.) was administered twice daily for two weeks , alone or jointly with one of the SSRIs. Concentrations of perazine and it s two main metabolites (N-desmethylperazine and 5-sulfoxide) in the plasma and brain were measured 30 min and 6 and 12 h after the last dose of the dr ugs. Of the investigated SSRIs, fluoxetine and fluvoxamine significantly in creased plasma and brain concentrations of perazine (up to 900 % and 760 % of the control value, respectively), their effect being most pronounced aft er 30 min and 6 h. Moreover, simultaneous increases in perazine metabolites concentrations and in the perazine/metabolite concentration ratios were ob served. Sertraline elevated plasma and brain concentrations of perazine aft er 30 min. In-vitro studies with liver microsomes of rats treated chronical ly with perazine, SSRIs or their combinations showed decreased concentratio ns of cytochrome P-450 after perazine and a combination of perazine and flu voxamine (vs control), and increased concentration after a combination of p erazine and fluoxetine (vs perazine-treated group). Prolonged treatment wit h perazine did not significantly change the rate of its own metabolism. Chr onic administration of fluoxetine or sertraline, alone or in a combination with perazine, accelerated perazine N-demethylation (vs control or perazine group, respectively). Fluvoxamine had a similar effect. The 5-sulfoxidatio n of perazine was accelerated by fluvoxamine and sertraline treatment, but the process was inhibited by administration of a combination of perazine an d fluoxetine or fluvoxamine (vs control). Kinetic studies using control liv er microsomes, in the absence or presence of SSRIs added in-vitro, demonstr ated competitive inhibition of both N-demethylation and sulfoxidation by th e investigated SSRIs. Sertraline was the most potent inhibitor of perazine N-demethylation but the weakest inhibitor of sulfoxidation. Results of in-v ivo and in-vitro studies indicate that the observed interaction between per azine and SSRIs mainly involves competition for an active site of perazine N-demethylase and sulfoxidase. Moreover, increases in the concentrations of both perazine and metabolites measured, produced by the investigated drug combinations in-vivo, suggest simultaneous inhibition of another, yet to be investigated, metabolic pathway of perazine (e.g. aromatic hydroxylation).