Objectives: We observed that CYP2D6 contributes to pharmacodynamic tissue sensitivity to perphenazine as measured by the areas under the curve (AUCs) expressed as a ratio (prolactin-AUC0-6/perphenazine-AUC0-6) in Chinese Canadians [Pharmacogenetics and Genomics 2007; 17:339-347]. As genetic heterogeneity in drug targets can influence drug response, we sought to further evaluate the contribution of CYP2D6 to pharmacodynamic sensitivity in our previous study sample in tandem with DRD2, the primary molecular target for perphenazine.
Methods: Genotyping for DRD2 Taq1A, -141C ins/del and Ser311Cys functional polymorphisms was performed using PCR-restriction-fragment length polymorphism methods.
Results: After controlling for DRD2 polymorphisms, CYP2D6 was a significant predictor of pituitary pharmacodynamic tissue sensitivity to perphenazine (P=0.024; power=80.4%). Taq1A polymorphism significantly influenced the time course of prolactin response (P=0.039; power=70%). A1/A1 genotype displayed a higher prolactin elevation 2 h after perphenazine administration (P=0.02). Patients with -141C ins/ins genotype showed a strong trend toward a 38% larger prolactin AUC compared with the -141C ins/del genotypic group (P=0.07).
Conclusions: CYP2D6 seems to be an independent contributor to pituitary pharmacodynamic tissue sensitivity to perphenazine after accounting for DRD2 functional polymorphisms. The A1 allele of the Taq1A polymorphism was previously shown to decrease D2 receptor density in vitro and in neuroimaging studies in vivo. At a given antipsychotic dose, individuals with A1 allele might thus achieve a higher DRD2 antipsychotic occupancy, which is consistent with an increased prolactin elevation in the A1/A1 genotype in this study. These findings provide a basis for further studies on the endogenous substrates of CYP2D6 and the rational selection of candidate genes for long-term consequences of antipsychotic-induced hyperprolactinemia (e.g. susceptibility to breast and prostate cancers).