Risperidone metabolism in relation to CYP2D6*10 allele in Korean schizophrenic patients.
OBJECTIVE
Risperidone is known to be biotransformed to its active metabolite, 9-hydroxyrisperidone, by the polymorphic CYP2D6 in Caucasians. This study aimed to investigate the relationship between the CYP2D6*10 allele and the plasma levels of risperidone and 9-hydroxyrisperidone in Korean schizophrenic patients.


METHODS
Eighty-two Korean schizophrenic patients in monotherapy with oral doses of risperidone from 1 mg/day to 8 mg/day (mean +/- SD 4.3 +/- 1.9, median 4) participated in this study. Plasma concentrations of risperidone and 9-hydroxyrisperidone were analyzed using high-performance liquid chromatography. The CYP2D6*10 allele, which contains C188T mutation in exon 1, was identified using allele-specific polymerase chain reaction amplification.


RESULTS
Seventeen of 82 patients were homozygous for CYP2D6*1, 22 for *10, while the remaining 43 patients were heterozygous for these alleles. The plasma levels of risperidone and 9-hydroxyrisperidone ranged from 1.0 nM to 168 nM and 6.2 nM to 235 nM, respectively. The median concentrations/dose (C/Ds) (range) of risperidone in CYP2D6*1/*1, *1/*10, and *10/*10 groups were 1.7 (0.2-7.9), 2.6 (0.3-27.1), and 6.7 nM/mg (2.4-21.0), respectively. There was a statistically significant difference among the three genotypes (Kruskal-Wallis test, P<0.001). For 9-hydroxyriperidone, the corresponding median C/Ds were 13.1 (3.3-25.4), 11.9 (4.2-30.8), and 13.6 nM/mg (6.5-52.8), respectively, with no significant difference between the genotypes (P=0.54). The medians of the ratios between risperidone and 9-hydroxyrisperidone concentrations were 0.13 (0.01-0.93), 0.28 (0.01-2.77), and 0.46 nM/mg (0.05-1.28) in *1/*1, *1/*10, and *10/*10 genotypes, respectively, and they were significantly different (P=0.004). The active moieties (sum of the C/Ds of risperidone and 9-hydroxyrisperidone) were not significantly different between the genotypes (P=0.063).


CONCLUSIONS
In Korean schizophrenic patients, the metabolism of risperidone is dependent on CYP2D6, and the CYP2D6*10 allele is important for the regulation of the activity of this enzyme. There were no significant differences in the plasma concentration of parent drug plus its active metabolite between the genotypes. This suggests that the clinical significance of this polymorphism is limited. Our study confirms previous studies on risperidone metabolism in Caucasians.
Roh
H K
HK
Department of Medical Laboratory Sciences and Toxicology, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden. keunroh@inha.ac.kr
Kim
C E
CE
Chung
W G
WG
Park
C S
CS
Svensson
J O
JO
Bertilsson
L
L
D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007723:Korea; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D018967:Risperidone / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*
D014150:Antipsychotic Agents; D019389:Cytochrome P-450 CYP2D6; D018967:Risperidone