title: Effects of CYP2D6 genotypes on plasma concentrations of risperidone and enantiomers of 9-hydroxyrisperidone in Japanese patients with schizophrenia.
abstract: It has been shown that risperidone (+)-9-hydroxylation is enantioselectively catalyzed by the polymorphic CYP2D6 in human liver. This study aimed to examine the effect of CYP2D6 genotype on (+)-9-hydroxylation of risperidone in schizophrenic patients. Subjects were 38 Japanese schizophrenic inpatients receiving 6 mg/day of risperidone. Plasma concentrations of risperidone and (+)- and (-)-9-hydroxyrisperidone at steady state were quantified using LC/MS/MS and HPLC with alpha 1 acid-AGP chiral column, respectively. The CYP2D6*5(*5) and *10 alleles were identified using polymerase chain reaction (PCR) methods. Twenty patients had no mutated allele, 14 had one mutated allele, and 4 had two mutated alleles. There were significant differences in the steady-state plasma concentrations of risperidone (ANOVA; p < 0.0001) among the three genotype groups, while the CYP2D6 genotype did not affect the steady-state plasma concentrations of (+)-9-hydroxyrisperidone (p = 0.314) or (-)-9-hydroxyrisperidone (p = 0.957). The concentration ratio of risperidone to 9-hydroxyrisperidone was strongly dependent on the CYP2D6 genotypes. This study suggests that CYP2D6 activity strongly influences the steady-state plasma concentrations of risperidone and risperidone/9-hydroxyrisperidone concentration ratios but is unlikely to determine enantio-selectivity in the steady-state plasma concentrations of 9-hydroxyrisperidone in the clinical situation.
authors.affiliation: Department of Clinical Pharmacology, Hirosaki University School of Medicine, Hirosaki, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Yasui-Furukori
authors.forename: Kazuo
authors.initials: K
authors.lastname: Mihara
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Kondo
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kubota
authors.forename: Tatsuji
authors.initials: T
authors.lastname: Iga
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Takarada
authors.forename: Ronald
authors.initials: R
authors.lastname: De Vries
authors.forename: Sunao
authors.initials: S
authors.lastname: Kaneko
authors.forename: Tomonori
authors.initials: T
authors.lastname: Tateishi
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019389:Cytochrome P-450 CYP2D6 / Q000145:classification / Q000235:genetics* / Q000494:pharmacology; D005260:Female; D005838:Genotype; D006207:Half-Life; D006801:Humans; D006900:Hydroxylation; D007555:Isoxazoles / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007564:Japan; D008297:Male; D000068882:Paliperidone Palmitate; D011743:Pyrimidines / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018967:Risperidone / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012559:Schizophrenia / Q000097:blood / Q000188:drug therapy*; D013237:Stereoisomerism
chemical_list: D014150:Antipsychotic Agents; D007555:Isoxazoles; D011743:Pyrimidines; D019389:Cytochrome P-450 CYP2D6; D018967:Risperidone; D000068882:Paliperidone Palmitate