title: CYP2D6 genotype in relation to perphenazine concentration and pituitary pharmacodynamic tissue sensitivity in Asians: CYP2D6-serotonin-dopamine crosstalk revisited.
abstract: OBJECTIVE
  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).
authors: Biomarker and Clinical Pharmacology Unit, VA Long Beach Medical Center, and School of Medicine, University of California-Irvine, 3844 East 15th Street, Long Beach, Irvine, CA 90804, USA. m.vural.ozdemir@gmail.com
authors: Vural
authors: V
authors: Ozdemir
authors: Leif
authors: L
authors: Bertilsson
authors: Jun
authors: J
authors: Miura
authors: Erin
authors: E
authors: Carpenter
authors: Christopher
authors: C
authors: Reist
authors: Patricia
authors: P
authors: Harper
authors: Jolanta
authors: J
authors: Widén
authors: Jan-Olof
authors: JO
authors: Svensson
authors: Lawrence J
authors: LJ
authors: Albers
authors: James L
authors: JL
authors: Kennedy
authors: Laszlo
authors: L
authors: Endrenyi
authors: Werner
authors: W
authors: Kalow
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000494:pharmacology*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D004298:Dopamine / Q000494:pharmacology; D015259:Dopamine Agents / Q000494:pharmacology; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008297:Male; D010546:Perphenazine / Q000494:pharmacology*; D010902:Pituitary Gland / Q000187:drug effects* / Q000378:metabolism; D010919:Placebos; D011110:Polymorphism, Genetic; D011388:Prolactin / Q000378:metabolism; D011446:Prospective Studies; D012701:Serotonin / Q000494:pharmacology; D018490:Serotonin Agents / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D015259:Dopamine Agents; D010919:Placebos; D018490:Serotonin Agents; D012701:Serotonin; D011388:Prolactin; D019389:Cytochrome P-450 CYP2D6; D010546:Perphenazine; D004298:Dopamine