title: The effect of selective serotonin reuptake inhibitors (SSRIs) on the pharmacokinetics and metabolism of perazine in the rat.
abstract: The aim of this study was to investigate the effect of three selective serotonin reuptake inhibitors (SSRIs), fluoxetine, fluvoxamine and sertraline, on the pharmacokinetics and metabolism of perazine in a steady state in rats. 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 its 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 drugs. Of the investigated SSRIs, fluoxetine and fluvoxamine significantly increased plasma and brain concentrations of perazine (up to 900% and 760% of the control value, respectively), their effect being most pronounced after 30 min and 6 h. Moreover, simultaneous increases in perazine metabolites concentrations and in the perazine/metabolite concentration ratios were observed. Sertraline elevated plasma and brain concentrations of perazine after 30 min. In-vitro studies with liver microsomes of rats treated chronically with perazine, SSRIs ortheir combinations showed decreased concentrations of cytochrome P-450 after perazine and a combination of perazine and fluvoxamine (vs control), and increased concentration after a combination of perazine and fluoxetine (vs perazine-treated group). Prolonged treatment with perazine did not significantly change the rate of its own metabolism. Chronic 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-sulfoxidation of perazine was accelerated by fluvoxamine and sertraline treatment, but the process was inhibited by administration of a combination of perazine and fluoxetine or fluvoxamine (vs control). Kinetic studies using control liver microsomes, in the absence or presence of SSRIs added in-vitro, demonstrated competitive inhibition of both N-demethylation and sulfoxidation by the investigated SSRIs. Sertraline was the most potent inhibitor of perazine N-demethylation but the weakest inhibitor of sulfoxidation. Results of in-vivo and in-vitro studies indicate that the observed interaction between perazine 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).
authors.affiliation: Polish Academy of Sciences, Institute of Pharmacology, Kraków. nfdaniel@cyf-kr.edu.pl
authors.forename: W A
authors.initials: WA
authors.lastname: Daniel
authors.forename: M
authors.initials: M
authors.lastname: Syrek
authors.forename: A
authors.initials: A
authors.lastname: Haduch
authors.forename: J
authors.initials: J
authors.lastname: Wójcikowski
mesh_terms: D000818:Animals; D001921:Brain; D018492:Dopamine Antagonists / Q000378:metabolism / Q000493:pharmacokinetics*; D004347:Drug Interactions; D005473:Fluoxetine / Q000494:pharmacology*; D016666:Fluvoxamine / Q000494:pharmacology*; D007263:Infusions, Parenteral; D008297:Male; D010464:Perazine / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D020280:Sertraline / Q000494:pharmacology*
chemical_list: D018492:Dopamine Antagonists; D005473:Fluoxetine; D016666:Fluvoxamine; D010464:Perazine; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline