CYP2D6 genotype in relation to perphenazine concentration and pituitary pharmacodynamic tissue sensitivity in Asians: CYP2D6-serotonin-dopamine crosstalk revisited.
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).
Ozdemir
Vural
V
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
Bertilsson
Leif
L
Miura
Jun
J
Carpenter
Erin
E
Reist
Christopher
C
Harper
Patricia
P
Widén
Jolanta
J
Svensson
Jan-Olof
JO
Albers
Lawrence J
LJ
Kennedy
James L
JL
Endrenyi
Laszlo
L
Kalow
Werner
W
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
D014150:Antipsychotic Agents; D015259:Dopamine Agents; D010919:Placebos; D018490:Serotonin Agents; D012701:Serotonin; D011388:Prolactin; D019389:Cytochrome P-450 CYP2D6; D010546:Perphenazine; D004298:Dopamine