title: Effect of risperidone metabolism and P-glycoprotein gene polymorphism on QT interval in patients with schizophrenia.
abstract: Risperidone (RIS) is a frequently used efficacious psychotropic drug. However, it prolongs the QTc interval and may cause fatal arrhythmia. Little is known on the determinants of this RIS side effect. RIS is metabolized by CYP2D6, and is subject to drug efflux by P-glycoprotein (P-gp) encoded by the ATP-binding cassette subfamily B member 1 (ABCB1) gene. P-gp removes both RIS and its metabolite 9-OH-RIS from cardiac tissue. To investigate the effect of RIS metabolism and ABCB1 gene polymorphisms on QTc, steady-state plasma RIS and 9-OH-RIS levels, and QTc were measured. CYP2D6, ABCB1 C3435T and G2677T/A genotypes were determined in 66 schizophrenia patients on RIS. QTc was significantly longer in patients with ABCB1 3435CT+3435 TT than in those with 3435CC (P=0.006). ABCB1 G2677T/A genotype did not affect QTc. Multiple regression analysis showed that C/T or T/T genotypes at the ABCB1 C3435T locus, lower weight, and older age prolonged QTc. In summary, the T allele of the ABCB1 C3435T genotype should be considered in future diagnostic development efforts for RIS-associated QT.
authors.affiliation: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Tsuneyama
authors.affiliation: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Fukui
authors.affiliation: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Sugai
authors.affiliation: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Watanabe
authors.affiliation: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Ono
authors.affiliation: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Saito
authors.affiliation: MP-Technopharma Corporation Technology Department, Fukuoka, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Inoue
authors.affiliation: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Someya
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000328:Adult; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use; D004562:Electrocardiography; D005260:Female; D006321:Heart / Q000503:physiopathology*; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic / Q000235:genetics*; D012044:Regression Analysis; D018967:Risperidone / Q000009:adverse effects* / Q000378:metabolism* / Q000627:therapeutic use; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D014150:Antipsychotic Agents; D018967:Risperidone