Serum concentrations of risperidone and aripiprazole in subgroups encoding CYP2D6 intermediate metabolizer phenotype.
BACKGROUND
Cytochrome P450 2D6 intermediate metabolizer phenotype (CYP2D6 IM) comprises various genotype subgroups. The aim of this study was to evaluate serum concentrations of the CYP2D6 substrates risperidone and aripiprazole in psychiatric patients with various CYP2D6 genotypes encoding IM phenotype.


METHODS
The study was based on therapeutic drug monitoring data from CYP2D6-genotyped patients (mainly of white origin) treated with orally administered risperidone (n = 190) or aripiprazole (n = 266). Patients were divided into 3 genotype subgroups encoding IM phenotype: (1) heterozygous carriers of fully functional and nonfunctional variant alleles (*1/def), (2) homozygous carriers of reduced-function variant alleles (red/red), and (3) heterozygous carriers of reduced-function and nonfunctional variant alleles (def/red). Dose-adjusted serum concentrations of risperidone and aripiprazole were compared between the genotype subgroups using *1/def, the most frequent CYP2D6 genotype among these subgroups, as the reference group.


RESULTS
Median serum concentrations were 4.5- and 1.6-fold higher in the def/red genotype than the *1/def genotype for risperidone and aripiprazole, respectively (P < 0.01 for both). Correspondingly, the serum concentrations were 3.4- and 1.8-fold higher in the red/red subgroup compared with the reference group (P < 0.05 for both).


CONCLUSIONS
In conclusion, this study revealed substantial variability in serum concentrations of risperidone and aripiprazole between CYP2D6 genotypes associated with IM phenotype. A considerable phenotypical difference was observed between patients carrying 1 and 2 variant alleles.
*Center for Psychopharmacology, Diakonhjemmet Hospital; and †Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway.
Magnhild
M
Hendset
Espen
E
Molden
Magnus
M
Knape
Monica
M
Hermann
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000068180:Aripiprazole; D002648:Child; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015363:Quinolones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012189:Retrospective Studies; D018967:Risperidone / Q000493:pharmacokinetics*; D055815:Young Adult
D014150:Antipsychotic Agents; D010879:Piperazines; D015363:Quinolones; D000068180:Aripiprazole; D019389:Cytochrome P-450 CYP2D6; D018967:Risperidone