Impact of the CYP2D6 genotype on steady-state serum concentrations of aripiprazole and dehydroaripiprazole.
OBJECTIVE
Aripiprazole is an atypical antipsychotic drug which is metabolized by the polymorphic enzyme cytochrome P450 2D6 (CYP2D6). The aim of the present study was to investigate the impact of the CYP2D6 genotype on serum concentrations of aripiprazole (ARI) and to determine the sum of ARI and the active metabolite dehydroaripiprazole (DARI) in psychiatric patients.


METHODS
Data on steady-state serum concentrations and the CYP2D6 genotypes of patients treated with ARI were extracted from a routine therapeutic drug monitoring database. The 62 patients included in the analysis were stratified into the following subgroups according to CYP2D6 genotype: *1/*1 (homozygous extensive metabolizers, EMs; n = 37), *1/*3-6 (heterozygous extensive metabolizers, HEMs; n = 17) and *3-6/*3-6 (poor metabolizers, PMs; n = 8). Dose-adjusted serum concentrations (C/D ratios) of ARI and ARI + DARI were compared between the subgroups.


RESULTS
The median serum concentration of ARI was 1.7-fold higher in PMs than in EMs (45.5 vs. 26.3 nM/mg, p < 0.01). The observed serum concentration of the active sum of ARI + DARI was 1.5-fold higher in PMs than in EMs (53.9 vs. 37.0 nM/mg, p < 0.05). Numerical differences in serum concentrations between HEMs and EMs were less pronounced, but statistically significant for both ARI (p < 0.05) and ARI + DARI (p < 0.05).


CONCLUSIONS
The present study demonstrates that serum concentrations of both ARI and the active sum of ARI + DARI in psychiatric patients were significantly affected by CYP2D6 genotype. The observed differences in median C/D ratios indicate that PMs typically need 30-40% lower doses to achieve a similar steady-state serum concentration as EMs.
Hendset
Magnhild
M
Department of Psychopharmacology, Diakonhjemmet Hospital, PO Box 85, Vinderen, 0319 Oslo, Norway. Magnhild.hendset@diakonsyk.no
Hermann
Monica
M
Lunde
Hilde
H
Refsum
Helge
H
Molden
Espen
E
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014150:Antipsychotic Agents / Q000097:blood*; D000068180:Aripiprazole; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D010879:Piperazines / Q000097:blood*; D015363:Quinolones / Q000097:blood*; D012189:Retrospective Studies