Ziprasidone and the activity of cytochrome P450 2D6 in healthy extensive metabolizers

Aims To determine whether ziprasidone alters the metabolizing activity of t he 2D6 isoenzyme of cytochrome P450 (CYP2D6). Methods Twenty-four healthy young subjects aged 18-45years were screened fo r CYP2D6 metabolizing activity and shown to be extensive metabolizers of de xtromethorphan. These subjects were then randomized to receive a single dos e of ziprasidone 80 mg, paroxetine 20 mg or placebo, 2 h before receiving a dose of dextromethorphan. Urine samples fbr the determination of dextromet horphan concentrations were collected over the 8 h period following dextrom ethorphan dosing, and used for the determination of dextromethorphan/dextro rphan ratios. Blood samples were collected immediately before and up to 10 h after the administration of ziprasidone or paroxetine, and used to derive pharmacokinetic parameters of ziprasidone and paroxetine. Results There were no statistically significant changes in the urinary dext romethorphan/dextrorphan ratio in the ziprasidone group or the placebo grou p. By contrast, there was a 10-fold increase in the urinary dextromethorpha n/dextrorphan ratio in the paroxetine group and this differed significantly from those in the ziprasidone and placebo groups (P = 0.0001). Conclusions The findings of this study suggest that ziprasidone does not in hibit the clearance of drugs metabolized by CYP2D6.