CYP2D6 genotype in relation to perphenazine concentration and pituitary pharmacodynamic tissue sensitivity in Asians: CYP2D6-serotonin-dopamine crosstalk revisited

Pharmacogenet Genomics. 2007 May;17(5):339-47. doi: 10.1097/FPC.0b013e32801a3c10.


Objectives: Hyperprolactinemia is a common side effect of first-generation antipsychotics mediated by antagonism of dopaminergic neurotransmission in the pituitary. Most first-generation antipsychotics are metabolized by CYP2D6 in the liver. Further, CYP2D6 is expressed in the human brain as a 5-methoxyindolethylamine O-demethylase potentially contributing to regeneration of serotonin from 5-methoxytryptamine. As dopaminergic neurotransmission is subject to regulation by serotonin, CYP2D6 may exert a nuanced (serotonergic) influence on dopaminergic tone in the pituitary. CYP2D6*10 is an allele associated with reduced enzyme function and occurs in high frequency (about 50%) in Asians. We prospectively evaluated significance of CYP2D6 genetic variation for prolactin response to perphenazine (a model first-generation antipsychotic) in Asians.

Methods: A single oral dose of perphenazine (0.1 mg/kg) or placebo was administered to 22 medication-free nonsmoker healthy male Chinese-Canadian volunteers, following a double-blind within-subject randomized design. Blood samples were drawn at baseline and 2, 3, 4, 5 and 6 h after drug administration.

Results: In volunteers with CYP2D6*10/CYP2D6*10 genotype, the mean area under curve (AUC0-6) for perphenazine concentration was 2.9-fold higher than those who carry the CYP2D6*1 allele (P<0.01). Notably, volunteers homozygous for CYP2D6*10 exhibited a significant reduction (66%) in mean pharmacodynamic tissue sensitivity as measured by the (prolactin-AUC0-6/perphenazine-AUC0-6) ratio (P=0.02).

Conclusions: CYP2D6 genotype is a significant contributor to perphenazine concentration in Chinese-Canadians. Importantly, prolactin response, when normalized per unit perphenazine concentration, appears to be blunted in volunteers homozygous for CYP2D6*10. We suggest that CYP2D6 genetic variation may potentially influence pharmacodynamic tissue sensitivity in the pituitary, presumably through disposition of an endogenous substrate (e.g. 5-methoxytryptamine).

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antipsychotic Agents / pharmacology*
  • Cytochrome P-450 CYP2D6 / genetics*
  • Cytochrome P-450 CYP2D6 / metabolism
  • Dopamine / pharmacology
  • Dopamine Agents / pharmacology
  • Double-Blind Method
  • Drug Interactions
  • Female
  • Genotype
  • Homozygote
  • Humans
  • Male
  • Perphenazine / pharmacology*
  • Pituitary Gland / drug effects*
  • Pituitary Gland / metabolism
  • Placebos
  • Polymorphism, Genetic*
  • Prolactin / metabolism
  • Prospective Studies
  • Serotonin / pharmacology
  • Serotonin Agents / pharmacology


  • Antipsychotic Agents
  • Dopamine Agents
  • Placebos
  • Serotonin Agents
  • Serotonin
  • Prolactin
  • Cytochrome P-450 CYP2D6
  • Perphenazine
  • Dopamine