title: QTc interval, CYP2D6 and CYP2C9 genotypes and risperidone plasma concentrations.
abstract: The role of certain drug metabolizing enzymes in cardiotoxicity, such as CYP2D6 for thioridazine, has been suggested. Risperidone has been shown to inhibit the delayed rectifier leading to lengthening of cardiac repolarization. The heart-rate corrected QT (QTc) interval lengthening has been reported in psychiatric patients receiving risperidone under steady-state conditions. CYP2D6 is involved in the metabolism of risperidone to 9-hydroxy (OH)-risperidone. CYP2C9 enzyme is also involved in the metabolism of several psychotropic drugs, although there are no data about its implication in risperidone metabolism. The present study aimed to evaluate the influence of CYP2D6 and CYP2C9 genotypes, and plasma concentrations of risperidone and 9-OH-risperidone on the QTc interval in patients under steady-state conditions. The relevance of CYP2D6 and CYP2C9 genotypes on risperidone metabolism was also analysed. Thirty-five White European psychiatric patients receiving risperidone monotherapy were studied. QTc interval was longer (p < 0.05) in subjects with one active CYP2D6 gene compared to those with two. The number of CYP2D6 active genes was related to the dose-corrected plasma concentration of risperidone (p < 0.05), the active moiety (risperidone plus 9-OH-risperidone) (p < 0.05) and the risperidone/9-OH-risperidone ratio (p < 0.05). CYP2C9 genotypes were not related to plasma concentrations of risperidone or 9-OH-risperidone, nor QTc interval. The results suggest that CYP2D6, but not CYP2C9, may be related to QTc lengthening during treatment with risperidone. The effect of the CYP2D6 genotype in risperidone metabolism is also shown.
authors.affiliation: Department of Pharmacology and Psychiatry, Faculty of Medicine, University of Extremadura, Badajoz, and Unit of Research and Clinical Psychopharmacology at Mérida Psychiatric Hospital, Mérida, Spain. allerena@unex.es
authors.forename: Adrián
authors.initials: A
authors.lastname: Llerena
authors.forename: Roland
authors.initials: R
authors.lastname: Berecz
authors.forename: Pedro
authors.initials: P
authors.lastname: Dorado
authors.forename: Alfredo
authors.initials: A
authors.lastname: de la Rubia
mesh_terms: D000284:Administration, Oral; D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D004334:Drug Administration Schedule; D004562:Electrocardiography / Q000187:drug effects; D005838:Genotype; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D008133:Long QT Syndrome / Q000139:chemically induced / Q000235:genetics*; D008875:Middle Aged; D000068882:Paliperidone Palmitate; D011743:Pyrimidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D018967:Risperidone / Q000097:blood* / Q000494:pharmacology
chemical_list: D007555:Isoxazoles; D011743:Pyrimidines; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D019389:Cytochrome P-450 CYP2D6; D018967:Risperidone; D000068882:Paliperidone Palmitate