Effects of the CYP2D6*10 alleles and co-medication with CYP2D6-dependent drugs on risperidone metabolism in patientswith schizophrenia

Objective: Risperidone is converted to 9-hydroxyrisperidone by CYP2D6. Two parameters were used to examine the influences of CYP2D6 polymorphism and of co-medication on risperidone metabolism: the risperidone:9-hydroxyrisperidone concentration ratio (R:9-OHR ratio) and the sum of the risperidone and 9-hydroxyrisperidone concentrations divided by the dose (C:D ratio). We evaluated the effect of the CYP2D6*10 allele, which is a prevalent mutant allele among East Asians. Methods: Genotyping using the P450 microarray system was performed for 89 Japanese patients with schizophrenia receiving risperidone. The patients with CYP2D6*1/*1, *1 /*2, or *2/*2 were classified as Group 1, those with one CYP2D6a10 allele (CYP2D6*1/2,10 or *2/*10) were classified as Group 2, and those with two CYP2D6,10 alleles were classified as Group 3. The R:9-OHR and C:D ratios were analyzed using two-way ANOVAs with the CYP2D6 genotype and co-medication with CYP2D6-dependent drugs as independent variables. Results: Both the "genotype" and the "co-medication" factors had significant impacts on the R:9-OHR ratio (p=0.011, p<0.001). The "genotype" factor also had a significant impact on the C:D ratio (p=0.032). However, the "co-medication" factor did not have a significant impact on the C:D ratio (p=0.129). Conclusions: The CYP2D6*10 polymorphism and the presence of co-medication exerted significant influences on the pharmacokinetics of risperidone.