Cytochrome P450 2D6 genotype and steady state plasma levels of risperidone and 9-hydroxyrisperidone

Abstract

The role of the polymorphic cytochrome P450 2D6 (CYP2D6) in the metabolism of risperidone to its major active metabolite, 9-hydroxyrisperidone (9-OH-risperidone), 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.

CYP2D6 genetic variation in healthy adults and psychiatric African-American subjects: implications for clinical practice and genetic testing

“…14 In this study, a new CYP2D6 allele (*58 allele) was identified as a result of the current testing efforts (GenBank accession #DQ282162). Whereas the poor metabolism phenotype in African-Americans is estimated to be only 2% based on currently confirmed null CYP2D6 alleles evaluated, 19 in vivo CYP2D6 activity measurements suggest that the frequency for poor metabolism in African-Americans may be closer to 7%.…”

“…37 The risperidone/9-OH ratio in patient plasma is dependent on CYP2D6 activity as 9-OH risperidone is formed by CYP2D6 metabolism of risperidone. 19,[38][39][40] It was notable that this ratio was not increased by the expression of the CYP2D6*17 allele in African-Americans (as would be expected for a CYP2D6 allele resulting in reduced activity), but rather decreased (Figure 1). This suggests the CYP2D6*17 allele may facilitate risperidone metabolism rather than diminish its metabolism.…”

“…The CYP2D6 enzyme has attracted substantial interest because of its role in the metabolism of many therapeutically important drugs, particularly those used to treat cardiovascular disease and psychiatric disorders. 8,[19][20][21] The purpose of this research was to characterize the CYP2D6 alleles and the frequency of each allele in African-Americans. This information was then used to define the criteria for CYP2D6 allele detection in AfricanAmerican subjects and what future research on CYP2D6 allele characterization remains to be carried out in this racial group.…”

Pharmacogenetics of risperidone therapy in autism: association analysis of eight candidate genes with drug efficacy and adverse drug reactions

“…10 In the liver, risperidone is extensively metabolized by CYP2D6 to the active metabolite 9-OH-risperidone. 11 The CYP2D6 gene is extremely polymorphic and its variants are classified, based on encoded protein activity level, into four different phenotypes, which have a profound influence in the outcome of drug therapy: (1) extensive metabolizers, carry one or two alleles with normal function; (2) intermediate metabolizers, carry two decreased-function alleles or are heterozygous for one deficient allele and one decreased-function allele; (3) poor metabolizers, carry two non-functional alleles; (4) ultrarapid metabolizers, carry multiple copies of functional alleles. 12 In the brain, risperidone binds multiple neurotransmitter receptors, with stronger affinity to the serotonin 2A (5-HT2A) and dopamine D2 receptors, and a good affinity for the a-1 and a-2C adrenergic receptors and for the serotonin receptors 6 and 7 (5-HT6 and 5-HT7).…”

Effect of fluvoxamine on plasma risperidone concentrations in patients with schizophrenia

“…According to in vivo and in vitro studies, cytochrome P450 (CYP) enzymes CYP2D6 and, to a lesser extent, CYP3A4 are responsible for the 9-hydroxylation of risperidone [4][5][6][7]. As 9-OH-risperidone is approximately equipotent with the parent drug in terms of dopamine receptor affinity, the total risperidone active moiety (risperidone plus 9-OH-risperidone) is regarded to contribute to the overall antipsychotic effect [8].…”