Impact of the CYP2D6 genotype on steady-state serum concentrations of aripiprazole and dehydroaripiprazole. 2007

Magnhild Hendset, and Monica Hermann, and Hilde Lunde, and Helge Refsum, and Espen Molden
Department of Psychopharmacology, Diakonhjemmet Hospital, PO Box 85, Vinderen, 0319 Oslo, Norway. Magnhild.hendset@diakonsyk.no

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.

UI MeSH Term Description Entries
D008297 Male Males
D008875 Middle Aged An adult aged 45 - 64 years. Middle Age
D010597 Pharmacogenetics A branch of genetics which deals with the genetic variability in individual responses to drugs and drug metabolism (BIOTRANSFORMATION). Pharmacogenomics
D010879 Piperazines Compounds that are derived from PIPERAZINE.
D005260 Female Females
D005838 Genotype The genetic constitution of the individual, comprising the ALLELES present at each GENETIC LOCUS. Genogroup,Genogroups,Genotypes
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000068180 Aripiprazole A piperazine and quinolone derivative that is used primarily as an antipsychotic agent. It is a partial agonist of SEROTONIN RECEPTOR, 5-HT1A and DOPAMINE D2 RECEPTORS, where it also functions as a post-synaptic antagonist, and an antagonist of SEROTONIN RECEPTOR, 5-HT2A. It is used for the treatment of SCHIZOPHRENIA and BIPOLAR DISORDER, and as an adjunct therapy for the treatment of depression. 7-(4-(4-(2,3-dichlorophenyl)-1-piperazinyl)butyloxy)-3,4-dihydro-2(1H)-quinolinone,Abilify,Aripiprazol,OPC 14597,OPC-14597
D000293 Adolescent A person 13 to 18 years of age. Adolescence,Youth,Adolescents,Adolescents, Female,Adolescents, Male,Teenagers,Teens,Adolescent, Female,Adolescent, Male,Female Adolescent,Female Adolescents,Male Adolescent,Male Adolescents,Teen,Teenager,Youths
D000328 Adult A person having attained full growth or maturity. Adults are of 19 through 44 years of age. For a person between 19 and 24 years of age, YOUNG ADULT is available. Adults

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