Individual differences in in vitro and in vivo metabolic clearances of antipsychotic risperidone from Japanese subjects genotyped for cytochrome P450 2D6 and 3A5
Individual differences in in vitro and in vivo metabolic clearances of antipsychotic risperidone from Japanese subjects genotyped for cytochrome P450 2D6 and 3A5
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DOI：
10.1002/hup.2516
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发表时间：
2016-03-01
影响因子：
1.7
通讯作者：
Yamazaki, Hiroshi
中科院分区：
文献类型：
--
作者：
Okubo, Maho;Morita, Shoko;Yamazaki, Hiroshi
关于细胞色素P450（P450，P450）基因型对临床患者利培酮及其代谢产物9-羟基利培酮（帕利哌酮）血药浓度的影响，有相互矛盾的报道。本研究的目的是调查个体差异的代谢清除利培酮在体外和invivo.MethodsIn体外肝微粒体利培酮9-羟基化活动和在体内血浆浓度的利培酮和帕潘立酮在15名男性和12名女性日本受试者进行了调查结果CYP 2D 6中、弱代谢者肝微粒体利培酮9-羟基化活性显著低于强代谢者;这种差异在50 μ M利培酮时不明显。重组CYP 3A 5对利培酮9-羟基化的V-max/K-m值是CYP 3A 4的30%，CYP 3A 5表达者的肝微粒体对利培酮9-羟基化的活性与CYP 3A 5低表达者相似。利培酮和帕潘立酮在27例日本患者的血浆浓度/剂量比没有显着影响的CYP 2D 6或CYP 3A 5 genotype.ConclusionsIndividual差异代谢清除率的利培酮在目前的条件下没有显着影响的CYP 2D 6或CYP 3A 5的基因型。版权所有（c）2016约翰威利父子有限公司
ObjectiveThere are conflicting reports regarding the effects of cytochrome P450 (P450, CYP) genotypes on the plasma concentrations of risperidone and its pharmacologically active metabolite, 9-hydroxyrisperidone (paliperidone), in clinical patients. The aim of this study was to investigate individual differences in the metabolic clearance of risperidone in vitro and in vivo.MethodsIn vitro liver microsomal risperidone 9-hydroxylation activities and in vivo plasma concentrations of risperidone and paliperidone were investigated in 15 male and 12 female Japanese subjects (mean age 52years, range: 24-75years) genotyped for CYP2D6 and CYP3A5.ResultsCYP2D6 intermediate and poor metabolizers showed significantly lower liver microsomal risperidone 9-hydroxylation activities than extensive metabolizers did at 5M of risperidone; this difference was not evident at 50M of risperidone. The recombinant CYP3A5 V-max/K-m value for risperidone 9-hydroxylation was 30% that of CYP3A4, and liver microsomes from CYP3A5 expressers had similar risperidone 9-hydroxylation activities to those of CYP3A5 poor expressers. The plasma concentration/dose ratios for risperidone and paliperidone in 27 Japanese patients were not significantly influenced by the CYP2D6 or CYP3A5 genotypes.ConclusionsIndividual differences in metabolic clearance of risperidone under the present conditions were not significantly influenced by the genotypes of CYP2D6 or CYP3A5. Copyright (c) 2016 John Wiley & Sons, Ltd.