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 evaluate s the importance of the CYP2D6 genotype for the disposition of the neu roleptic agents perphenazine and zuclopenthixol. Methods: Patients tre ated 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 individ ual kinetic modeling, a bayesian approach was used for determination o f the clearance, Population kinetic parameters for this procedure were collected from retrospective therapeutic drug monitoring data. (n = 1 13) by use of a nonparametric approach. Results: The CYP2D6 genotype s ignificantly predicted the oral clearance of perphenazine and zuclopen thixol (p < 0.01 by multiple regression), The difference in clearance between homozygous extensive metabolizers and poor metabolizers was th reefold for perphenazine and twofold for zuclopenthixol. Conclusion: T he results show that the genotype for CYP2D6 is closely related to the oral clearances of perphenazine and zuclopenthixol. If this finding c an be confirmed in a larger population, genotyping may become an impor tant tool for the dosing of these two neuroleptic agents.