The CYP2D6 genotype predicts the oral clearance of the neuroleptic agents perphenazine and zuclopenthixol.
BACKGROUND
Most antidepressant and neuroleptic agents are metabolized by the polymorphic cytochrome P450 enzyme CYP2D6. This study evaluates the importance of the CYP2D6 genotype for the disposition of the neuroleptic agents perphenazine and zuclopenthixol.


METHODS
Patients treated with neuroleptic agents (n = 36) were studied prospectively with regard to CYP2D6 genotype and neuroleptic plasma concentration during oral treatment. Because no patient provided enough samples for individual kinetic modeling, a bayesian approach was used for determination of the clearance. Population kinetic parameters for this procedure were collected from retrospective therapeutic drug monitoring data (n = 113) by use of a nonparametric approach.


RESULTS
The CYP2D6 genotype significantly predicted the oral clearance of perphenazine and zuclopenthixol (p < 0.01 by multiple regression). The difference in clearance between homozygous extensive metabolizers and poor metabolizers was threefold for perphenazine and twofold for zuclopenthixol.


CONCLUSIONS
The results show that the genotype for CYP2D6 is closely related to the oral clearances of perphenazine and zuclopenthixol. If this finding can be confirmed in a larger population, genotyping may become an important tool for the dosing of these two neuroleptic agents.
Jerling
M
M
Department of Clinical Pharmacology, Karolinska Institute, Huddinge Hospital, Sweden.
Dahl
M L
ML
Aberg-Wistedt
A
A
Liljenberg
B
B
Landell
N E
NE
Bertilsson
L
L
Sjöqvist
F
F
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001499:Bayes Theorem; D003006:Clopenthixol / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019389:Cytochrome P-450 CYP2D6; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D010546:Perphenazine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011446:Prospective Studies
D014150:Antipsychotic Agents; D003577:Cytochrome P-450 Enzyme System; D003006:Clopenthixol; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; D010546:Perphenazine