Cytochrome P450 2D6 genotype and steady state plasma levels of risperidone and 9-hydroxyrisperidone |
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| Authors: | Maria Gabriella Scordo Edoardo Spina Gabriella Facciolà Angela Avenoso Inger Johansson Marja-Liisa Dahl |
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| Institution: | (1) Institute of Pharmacology, University of Messina, Messina, Italy, IT;(2) Department of Medical Laboratory Sciences and Technology, Division of Clinical Pharmacology, Karolinska Institutet, Huddinge University Hospital, Huddinge, Sweden, SE;(3) Centers of Mental Health, A.S.L. 5, Messina, Italy, IT;(4) Institute of Environmental Medicine, Division of Molecular Toxicology, Karolinska Institutet, Stockholm, Sweden, SE;(5) Department of Clinical Pharmacology, Huddinge University Hospital, S-141 86 Huddinge, Sweden e-mail: Marja-Liisa.Dahl@pharmlab.hs.sll.se, Fax: +46-8-585-81070, SE |
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| 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.
Received: 3 March 1999 / Final version: 28 June 1999 |
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| Keywords: | Risperidone 9-Hydroxyrisperidone CYP2D6 genotype Steady-state plasma concentration Genetic polymorphism |
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