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Titolo:
Cytochrome P450 2D6 genotype and steady state plasma levels of risperidoneand 9-hydroxyrisperidone
Autore:
Scordo, MG; Spina, E; Facciola, G; Avenoso, A; Johansson, I; Dahl, ML;
Indirizzi:
Huddinge Univ Hosp, Dept Clin Pharmacol, S-14186 Huddinge, Sweden HuddingeUniv Hosp Huddinge Sweden S-14186 col, S-14186 Huddinge, Sweden Univ Messina, Inst Pharmacol, Messina, Italy Univ Messina Messina ItalyUniv Messina, Inst Pharmacol, Messina, Italy Huddinge Univ Hosp, Karolinska Inst, Div Clin Pharmacol, Dept Med Lab Sci & Technol, S-14186 Huddinge, Sweden Huddinge Univ Hosp Huddinge Sweden S-14186 nol, S-14186 Huddinge, Sweden Ctr Mental Hlth, Messina, Italy Ctr Mental Hlth Messina ItalyCtr Mental Hlth, Messina, Italy Karolinska Inst, Inst Environm Med, Div Mol Toxicol, S-10401 Stockholm, Sweden Karolinska Inst Stockholm Sweden S-10401 icol, S-10401 Stockholm, Sweden
Titolo Testata:
PSYCHOPHARMACOLOGY
fascicolo: 3, volume: 147, anno: 1999,
pagine: 300 - 305
Fonte:
ISI
Lingua:
ENG
Soggetto:
POLYMORPHIC HYDROXYLATION; POOR METABOLIZERS; DEBRISOQUIN HYDROXYLATION; SWEDISH POPULATION; CYP2D6 GENE; PHENOTYPE; OXIDATION; DISPOSITION; ALLELE; AMPLIFICATION;
Keywords:
risperidone; 9-hydroxyrisperidone; CYP2D6 genotype; steady-state plasma concentration; genetic polymorphism;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
37
Recensione:
Indirizzi per estratti:
Indirizzo: Dahl, ML Huddinge Univ Hosp, Dept Clin Pharmacol, S-14186 Huddinge, SwedenHuddinge Univ Hosp Huddinge Sweden S-14186 186 Huddinge, Sweden
Citazione:
M.G. Scordo et al., "Cytochrome P450 2D6 genotype and steady state plasma levels of risperidoneand 9-hydroxyrisperidone", PSYCHOPHAR, 147(3), 1999, pp. 300-305

Abstract

The role of the polymorphic cytochrome P450 2D6 (CYP2D6) in the metabolismof 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 theCYP2D6 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 similarpharmacological 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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Documento generato il 25/01/20 alle ore 18:49:09