Effect of polymorphisms on the pharmacokinetics, pharmacodynamics, and safety of risperidone in healthy volunteers

IF 1.7 4区医学 Q3 CLINICAL NEUROLOGY

Human Psychopharmacology: Clinical and Experimental Pub Date : 2014-07-09 DOI:10.1002/hup.2420

Teresa Cabaleiro, Dolores Ochoa, Rosario López-Rodríguez, Manuel Román, Jesús Novalbos, Carmen Ayuso, Francisco Abad-Santos

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引用次数: 36

Abstract

Objective

To identify genetic markers capable of predicting the pharmacokinetics, pharmacodynamics, and adverse effects of risperidone.

Methods

Genotyping was performed in 70 healthy volunteers receiving a single 1 mg oral dose of risperidone. Risperidone and hydroxyrisperidone plasma levels were measured using high-performance liquid chromatography combined with tandem mass spectrometry. Prolactin concentration was quantified by direct chemiluminescence.

Results

Poor CYP2D6 metabolizers showed higher risperidone C_max, area under the curve (AUC), and t_1/2, as well as lower clearance. They also showed lower C_max and AUC and higher t_1/2 for hydroxyrisperidone. Furthermore, individuals with a mutant VKORC1 genotype had a lower risperidone AUC and t_1/2 and higher clearance. The hydroxyrisperidone AUC was lower in individuals with the COMT mutant genotype. Risperidone increased prolactin levels (iAUC and iC_max), which were higher in women than in men. The most frequent reactions were somnolence (47.1%), headache (21.4%), and dizziness (17.1%). Women had neurological effects and headache more frequently than men. The incidence of headache was associated with polymorphisms in the AGTR1 and NAT2; neurological effects were associated with CYP2C19.

Conclusions

Differences in the pharmacokinetics of risperidone are due to polymorphisms in CYP2D6, COMT, and VKORC1. Differences in adverse reactions can be explained by gender and polymorphisms in CYP2C19, AGTR1, and NAT2. Copyright © 2014 John Wiley & Sons, Ltd.

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健康志愿者体内基因多态性对利培酮药代动力学、药效学和安全性的影响

目的寻找能够预测利培酮药代动力学、药效学和不良反应的遗传标记。方法对70例健康志愿者口服利培酮1 mg进行基因分型。采用高效液相色谱联合串联质谱法测定利培酮和羟利培酮的血浆水平。用直接化学发光法测定催乳素浓度。结果CYP2D6代谢不良者利培酮Cmax、曲线下面积(AUC)、t1/2较高，清除率较低。羟基利培酮的Cmax和AUC较低，t1/2较高。此外，突变VKORC1基因型个体的利培酮AUC和t1/2较低，清除率较高。COMT突变基因型个体的羟利培酮AUC较低。利培酮增加催乳素水平(iAUC和iCmax)，女性高于男性。最常见的反应是嗜睡(47.1%)、头痛(21.4%)和头晕(17.1%)。女性出现神经系统疾病和头痛的频率高于男性。头痛的发生与AGTR1和NAT2基因多态性有关;神经学效应与CYP2C19相关。结论利培酮的药代动力学差异是由于CYP2D6、COMT和VKORC1基因多态性所致。不良反应的差异可以用性别和CYP2C19、AGTR1和NAT2基因的多态性来解释。版权所有©2014 John Wiley &儿子,有限公司

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来源期刊

Human Psychopharmacology: Clinical and Experimental 医学-精神病学

CiteScore

4.10

自引率

0.00%

发文量

审稿时长

6-12 weeks

期刊介绍： Human Psychopharmacology: Clinical and Experimental provides a forum for the evaluation of clinical and experimental research on both new and established psychotropic medicines. Experimental studies of other centrally active drugs, including herbal products, in clinical, social and psychological contexts, as well as clinical/scientific papers on drugs of abuse and drug dependency will also be considered. While the primary purpose of the Journal is to publish the results of clinical research, the results of animal studies relevant to human psychopharmacology are welcome. The following topics are of special interest to the editors and readers of the Journal: -All aspects of clinical psychopharmacology- Efficacy and safety studies of novel and standard psychotropic drugs- Studies of the adverse effects of psychotropic drugs- Effects of psychotropic drugs on normal physiological processes- Geriatric and paediatric psychopharmacology- Ethical and psychosocial aspects of drug use and misuse- Psychopharmacological aspects of sleep and chronobiology- Neuroimaging and psychoactive drugs- Phytopharmacology and psychoactive substances- Drug treatment of neurological disorders- Mechanisms of action of psychotropic drugs- Ethnopsychopharmacology- Pharmacogenetic aspects of mental illness and drug response- Psychometrics: psychopharmacological methods and experimental design