PAROXETINE POTENTIATES THE CENTRAL-NERVOUS-SYSTEM SIDE-EFFECTS OF PERPHENAZINE - CONTRIBUTION OF CYTOCHROME P4502D6 INHIBITION IN-VIVO

Background: Paroxetine is a frequently used antidepressant and a poten t inhibitor of the CYP2D6 isozyme in vitro (inhibition constant [K-i] = 0.15 mu mol/L). Most classic antipsychotic agents such as perphenazi ne are metabolized by the CYP2D6 isozyme and are often coadministered with antidepressant agents, This study assessed the extent of changes in CYP2D6 isozyme activity in vivo after pretreatment with paroxetine and its consequences on perphenazine kinetics and central nervous syst em effects. Methods: Eight extensive metabolizers for CYP2D6 were admi nistered a single dose of perphenazine (0.11 mg/kg orally) or placebo following a randomized double-blind design, Perphenazine plasma concen trations and effects were assessed for a period of 8 hours. Subsequent ly, subjects were treated with a standard therapeutic dose of paroxeti ne (20 mg/day orally) for 10 days and test sessions with perphenazine and placebo were repeated. Results: Paroxetine treatment resulted in a twofold to 21-fold decrease in CYP2D6 activity (p < 0.001), After pre treatment with paroxetine, perphenazine peak plasma concentrations inc reased twofold to 13-fold (p < 0.01). This was associated with a signi ficant increase in central nervous system side effects of perphenazine , including oversedation, extrapyramidal symptoms, and impairment of p sychomotor performance and memory (p < 0.05). Conclusion: Coadministra tion of perphenazine after pretreatment with a standard therapeutic do se of paroxetine increased the plasma concentration and central nervou s system side effects of perphenazine, primarily as a result of inhibi tion of the CYP2D6 isozyme, In patients who are at steady state with p aroxetine, a reduction of perphenazine dose may be required to prevent central nervous system side effects.