The role of the polymorphic cytochrome P450 2D6 (CYP2D6) in the metabolism of risperidone to its major active metabolite, 9-hydroxyrisperidone (9-OHrisperidone), has been documented after single oral doses of the drug. In this study, the influence of the CYP2D6 polymorphism on the steady-state plasma concentrations of risperidone and 9-OH-risperidone was investigated. Thirty-seven schizophrenic patients on monotherapy with risperidone, 4–8 mg/day, were genotyped by RFLP and PCR for the major functional variants of the CYP2D6 gene. Steady state plasma levels of risperidone and 9-OH-risperidone were analysed by HPLC. Based on the genotype analysis, three patients were classified as ultrarapid metabolizers (UM) with an extra functional CYP2D6 gene, 16 were homozygous extensive metabolizers (EM), 15 heterozygous EM and three poor metabolizers (PM). The median steady-state plasma concentration- to-dose (C/D) ratios of risperidone were 0.6, 1.1, 9.7 and 17.4 nmol/l per mg in UM, homozygous EM, heterozygous EM and PM, respectively, with statistically significant differences between PM and the other genotypes (P<0.02). The C/D of 9-OH-risperidone also varied widely but was not related to the genotype. The risperidone/ 9-OH-risperidone ratio was strongly associated with the CYP2D6 genotype, with the highest ratios in PM (median 0.79). Heterozygous EM also had significantly higher ratios than homozygous EM (median value 0.23 versus 0.04; P<0.01) or UM (median 0.03; P<0.02). No significant differences were found in the C/D of the sum of the plasma concentrations of risperidone and 9-OH-risperidone between the genotype groups. In conclusion, the steady-state plasma concentrations of risperidone and the risperidone/9-OH-risperidone ratio are highly dependent on the CYP2D6 genotype. However, as risperidone and 9-OH-risperidone are considered to have similar pharmacological activity, the lack of relationship between the genotype and the sum of risperidone and 9-OH-risperidone indicates that the CYP2D6 polymorphism may be of limited importance for the clinical outcome of the treatment.
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