Llerena Adrián, Berecz Roland, Dorado Pedro, de la Rubia Alfredo
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.
J Psychopharmacol. 2004 Jun;18(2):189-93. doi: 10.1177/0269881104042618.
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.
某些药物代谢酶在心脏毒性中的作用已被提及，比如硫利达嗪的CYP2D6。已有研究表明，利培酮可抑制延迟整流器，导致心脏复极化延长。在稳态条件下接受利培酮治疗的精神科患者中，已报告出现心率校正QT（QTc）间期延长。CYP2D6参与利培酮代谢生成9-羟基（OH）-利培酮。CYP2C9酶也参与多种精神药物的代谢，不过尚无关于其在利培酮代谢中作用的数据。本研究旨在评估CYP2D6和CYP2C9基因分型以及利培酮和9-OH-利培酮的血浆浓度对稳态条件下患者QTc间期的影响。还分析了CYP2D6和CYP2C9基因分型对利培酮代谢的相关性。对35例接受利培酮单药治疗的欧洲白人精神科患者进行了研究。与拥有两个活性CYP2D6基因的受试者相比，拥有一个活性CYP2D6基因的受试者的QTc间期更长（p<0.05）。CYP2D6活性基因的数量与利培酮的剂量校正血浆浓度（p<0.05）、活性部分（利培酮加9-OH-利培酮）（p<0.05）以及利培酮/9-OH-利培酮比值（p<0.05）相关。CYP2C9基因分型与利培酮或9-OH-利培酮的血浆浓度以及QTc间期均无关联。结果表明，CYP2D6而非CYP2C9可能与利培酮治疗期间的QTc延长有关。还显示了CYP2D6基因分型在利培酮代谢中的作用。
