Vanwong Natchaya, Ngamsamut Nattawat, Medhasi Sadeep, Puangpetch Apichaya, Chamnanphon Montri, Tan-Kam Teerarat, Hongkaew Yaowaluck, Limsila Penkhae, Sukasem Chonlaphat
1 Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University , Bangkok, Thailand .
2 Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC) , Ramathibodi Hospital, Bangkok, Thailand .
J Child Adolesc Psychopharmacol. 2017 Mar;27(2):185-191. doi: 10.1089/cap.2014.0171. Epub 2016 Jan 18.
The purpose of this study was to investigate the influence of CYP2D6 gene polymorphisms on plasma concentrations of risperidone and its metabolite in Thai children and adolescents with autism spectrum disorder (ASD).
All 97 autism spectrum disorder patients included in this study had been receiving risperidone at least for 1 month. The CYP2D6 genotypes were determined by real-time polymerase chain reaction (PCR)-based allelic discrimination for CYP2D6*4, *10, and *41 alleles. Plasma concentrations of risperidone and 9-hydroxyrisperidone were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS).
Among the 97 patients, the most important nonfunctional alleles (CYP2D64 and 5) were detected, whereas the most common allele was CYP2D610 (55.9%). CYP2D6 genotyping revealed 90 (92.78%) patients to be extensive metabolizers (EM) and 7 (7.22%) to be intermediate metabolizers (IM). Plasma levels of risperidone were significantly higher in individuals with CYP2D65/10 (p = 0.02), CYP2D610/10 (p = 0.04), and CYP2D610/*41 (p = 0.04). Additionally, the plasma concentration of risperidone/9-OH risperidone ratio in patients with a CYP2D6 activity score of 0.5 were significantly higher than those with a CYP2D6 activity score of 2 (p = 0.04). Conversely, no significant influence was found among CYP2D6 polymorphisms, plasma concentrations of 9-hydroxyrisperidone, and the total active moiety.
This is the first study to investigate the effects of CYP2D6 genetic polymorphisms on the plasma concentrations of risperidone in Thai children with ASD. The findings indicate that CYP2D6 polymorphisms affect the plasma concentrations of risperidone and the risperidone/9-hydroxyrisperidone ratio. Genetic screening for CYP2D6 polymorphisms could help to predict unexpected adverse events caused by the higher plasma concentration of risperidone.
本研究旨在调查细胞色素P450 2D6（CYP2D6）基因多态性对泰国自闭症谱系障碍（ASD）儿童和青少年血浆中利培酮及其代谢物浓度的影响。
本研究纳入的97例自闭症谱系障碍患者均已接受利培酮治疗至少1个月。通过基于实时聚合酶链反应（PCR）的等位基因鉴别法测定CYP2D6*4、10和41等位基因的CYP2D6基因型。采用液相色谱-串联质谱法（LC-MS/MS）测定血浆中利培酮和9-羟基利培酮的浓度。
在97例患者中，检测到了最重要的无功能等位基因（CYP2D64和5），而最常见的等位基因是CYP2D610（55.9%）。CYP2D6基因分型显示，90例（92.78%）患者为广泛代谢型（EM），7例（7.22%）为中间代谢型（IM）。携带CYP2D65/10（p = 0.02）、CYP2D610/10（p = 0.04）和CYP2D610/*41（p = 0.04）的个体血浆中利培酮水平显著更高。此外，CYP2D6活性评分为0.5的患者血浆中利培酮/9-羟基利培酮比值显著高于CYP2D6活性评分为2 的患者（p = 0.04）。相反，未发现CYP2D6基因多态性、9-羟基利培酮血浆浓度和总活性部分之间存在显著影响。
这是第一项调查CYP2D6基因多态性对泰国ASD儿童血浆中利培酮浓度影响的研究。研究结果表明，CYP2D6基因多态性会影响血浆中利培酮的浓度以及利培酮/9-羟基利培酮比值。对CYP2D6基因多态性进行基因筛查有助于预测因血浆中利培酮浓度升高导致的意外不良事件。
