BACKGROUND & AIMS:
: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.
背景与目标:
:利培酮主要通过细胞色素P450酶CYP2D6和3A4代谢成其活性代谢物9-羟基利培酮。假定其抗精神病作用与活性部分有关,即利培酮和9-羟基利培酮的总和。利培酮和9-羟基利培酮都是P-糖蛋白(P-gp)的底物,P-gp是一种涉及药物吸收,分布和消除的转运蛋白。本研究的目的是在考虑CYP2D6基因型状态的情况下,评估CYP3A5和P-gp(ABCB1)编码基因多态性对利培酮,9-羟基利培酮和活性成分的稳态血浆水平的影响。对46例接受利培酮(1-10 mg / d)单一治疗4-6周的精神分裂症白人患者进行基因分型,并测定其血浆中利培酮和9-羟基利培酮的浓度。利培酮,9-羟基利培酮和活性部分的剂量校正血浆浓度(C / D)分别显示高达68倍,9倍和10倍的个体差异。 6名患者携带1个CYP3A5 * 1等位基因,因此可能表达CYP3A5酶。 CYP3A5基因型不影响利培酮,9-羟基利培酮或活性部分C / D。 CYP2D6基因型在这46例患者中再次与利培酮C / D相关(P = 0.001),但与9-羟基利培酮C / D或活性成分C / D不相关,正如我们小组中先前在这些患者中的37名所示。与携带其他ABCB1基因型的患者相比,纯合ABCB1 3435T / 2677T / 1236T单倍型的患者的9-羟基利培酮(C = 0.026)和活性部分(P = 0.028)的C / D显着降低。总之,我们的结果证实了CYP2D6基因型对利培酮的稳态血浆水平具有显着影响,并表明ABCB1多态性对9-羟基利培酮和活性成分的中度影响中等。