title: ABCB1 polymorphisms influence steady-state plasma levels of 9-hydroxyrisperidone and risperidone active moiety.
abstract: Risperidone is metabolized to its active metabolite, 9-hydroxyrisperidone, mainly by the cytochrome P450 enzymes CYP2D6 and 3A4. Its antipsychotic effect is assumed to be related to the active moiety, that is, the sum of risperidone and 9-hydroxyrisperidone. Both risperidone and 9-hydroxyrisperidone are substrates of P-glycoprotein (P-gp), a transport protein involved in drug absorption, distribution, and elimination. The aim of the present study was to evaluate the influence of polymorphisms in genes encoding CYP3A5 and P-gp (ABCB1) on the steady-state plasma levels of risperidone, 9-hydroxyrisperidone, and the active moiety, taking CYP2D6 genotype status into account. Forty-six white patients with schizophrenia treated with risperidone (1-10 mg/d) in monotherapy for 4-6 weeks were genotyped, and their plasma concentrations of risperidone and 9-hydroxyrisperidone were measured. Dose-corrected plasma concentrations (C/D) of risperidone, 9-hydroxyrisperidone, and active moiety showed up to 68-, 9-, and 10-fold interindividual variation, respectively. Six patients carried 1 CYP3A5*1 allele and therefore were likely to express the CYP3A5 enzyme. The CYP3A5 genotype did not influence risperidone, 9-hydroxyrisperidone, or active moiety C/Ds. The CYP2D6 genotype in these 46 patients was again associated with risperidone C/D (P = 0.001) but not with 9-hydroxyrisperidone C/D or active moiety C/D, as previously shown by our group in 37 of these patients. Patients homozygous for the ABCB1 3435T/2677T/1236T haplotype had significantly lower C/Ds of 9-hydroxyrisperidone (P = 0.026) and active moiety (P = 0.028) than patients carrying other ABCB1 genotypes. In conclusion, our results confirmed the significant effect of CYP2D6 genotype on the steady-state plasma levels of risperidone and showed that ABCB1 polymorphisms have a moderate effect on those of 9-hydroxyrisperidone and the active moiety.
authors: Department of Medical Sciences, Clinical Pharmacology, Uppsala University, Uppsala, Sweden.
authors: Arzu
authors: A
authors: Gunes
authors: Edoardo
authors: E
authors: Spina
authors: Marja-Liisa
authors: ML
authors: Dahl
authors: Maria Gabriella
authors: MG
authors: Scordo
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D000483:Alleles; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000097:blood / Q000235:genetics; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007555:Isoxazoles / Q000097:blood*; D008297:Male; D008875:Middle Aged; D000068882:Paliperidone Palmitate; D011110:Polymorphism, Genetic / Q000235:genetics*; D011743:Pyrimidines / Q000097:blood*; D018967:Risperidone / Q000097:blood*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007555:Isoxazoles; D011743:Pyrimidines; C510164:CYP3A5 protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D018967:Risperidone; D000068882:Paliperidone Palmitate