Ziprasidone and the activity of cytochrome P450 2D6 in healthy extensive metabolizers.
OBJECTIVE
To determine whether ziprasidone alters the metabolizing activity of the 2D6 isoenzyme of cytochrome P450 (CYP2D6).


METHODS
Twenty-four healthy young subjects aged 18-45 years were screened for CYP2D6 metabolizing activity and shown to be extensive metabolizers of dextromethorphan. These subjects were then randomized to receive a single dose of ziprasidone 80 mg, paroxetine 20 mg or placebo, 2 h before receiving a dose of dextromethorphan. Urine samples for the determination of dextromethorphan concentrations were collected over the 8 h period following dextromethorphan dosing, and used for the determination of dextromethorphan/dextrorphan 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 dextromethorphan/dextrorphan ratio in the ziprasidone group or the placebo group. By contrast, there was a 10-fold increase in the urinary dextromethorphan/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 inhibit the clearance of drugs metabolized by CYP2D6.
Wilner
K D
KD
Department of Clinical Research, Pfizer Central Research, Groton, CT 06340, USA.
Demattos
S B
SB
Anziano
R J
RJ
Apseloff
G
G
Gerber
N
N
D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003915:Dextromethorphan / Q000493:pharmacokinetics; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017374:Paroxetine / Q000097:blood / Q000494:pharmacology; D010879:Piperazines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000097:blood / Q000494:pharmacology; D013844:Thiazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*
D014150:Antipsychotic Agents; D019389:Cytochrome P-450 CYP2D6; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003915:Dextromethorphan; D004791:Enzyme Inhibitors; D017374:Paroxetine; D010879:Piperazines; D017367:Selective Serotonin Reuptake Inhibitors; D013844:Thiazoles; C092292:ziprasidone