Fang Chao, Ouyang Wen, Zeng Youjie, Pei Qi, Xia Yuhao, Luo Siwan, Chen Minghua
Department of Anesthesiology, Third Xiangya Hospital, Central South University, Changsha, China.
Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.
Front Pharmacol. 2022 Jul 7;13:943200. doi: 10.3389/fphar.2022.943200. eCollection 2022.
Dexmedetomidine is a commonly used clinical sedative; however, the drug response varies among individuals. Thus, the purpose of this study was to explore the association between dexmedetomidine response and gene polymorphisms related to drug-metabolizing enzymes and drug response (, , , , , , , , and ). This study was a prospective cohort study. A total of 194 female patients aged 18-60 years, American Society of Anesthesiologists (ASA) score I-II, who underwent laparoscopy at the Third Xiangya Hospital of Central South University, were included. The sedative effect was assessed every 2 min using the Ramsay score, and the patient's heart rate decrease within 20 min was recorded. Peripheral blood was collected from each participant to identify genetic variants in the candidate genes of metabolic and drug effects using the Sequenom MassARRAY platform. Furthermore, additional peripheral blood samples were collected from the first 99 participants at multiple time points after dexmedetomidine infusion to perform dexmedetomidine pharmacokinetic analysis by Phoenix WinNonlin 7.0 software. Carriers of the minor allele (C) of rs28399433 had lower metabolic enzyme efficiency and higher plasma concentrations of dexmedetomidine. In addition, the participants were divided into dexmedetomidine sensitive or dexmedetomidine tolerant groups based on whether they had a Ramsay score of at least four within 20 min, and rs28399433 was identified to have a significant influence on the dexmedetomidine sedation sensitivity by logistic regression with Plink software [ = 0.003, OR (95% CI): 0.27 (0.11-0.65)]. C allele carriers were more sensitive to the sedative effects of dexmedetomidine than A allele carriers. rs279847 polymorphism was significantly associated with the degree of the heart rate decrease. In particular, individuals with the GG genotype had a 4-fold higher risk of heart rate abnormality than carriers of the T allele (OR = 4.32, 95% CI: 1.96-9.50, = 0.00027). rs28399433 polymorphism affects the metabolic rate of dexmedetomidine and is associated with susceptibility to the sedative effects of dexmedetomidine; rs279847 polymorphism is significantly associated with the degree of the heart rate decrease.
右美托咪定是一种常用的临床镇静剂；然而，个体之间的药物反应存在差异。因此，本研究的目的是探讨右美托咪定反应与药物代谢酶和药物反应相关基因多态性之间的关联（，，，，，，，，和）。本研究为前瞻性队列研究。纳入了中南大学湘雅三医院194例年龄在18 - 60岁、美国麻醉医师协会（ASA）评分I - II级、接受腹腔镜手术的女性患者。每2分钟使用 Ramsay评分评估镇静效果，并记录患者20分钟内的心率下降情况。采集每位参与者的外周血，使用Sequenom MassARRAY平台鉴定代谢和药物作用候选基因中的基因变异。此外，在右美托咪定输注后的多个时间点，从最初的99名参与者中采集额外的外周血样本，使用Phoenix WinNonlin 7.0软件进行右美托咪定药代动力学分析。rs28399433次要等位基因（C）的携带者代谢酶效率较低，右美托咪定血浆浓度较高。此外，根据参与者在20分钟内Ramsay评分是否至少为4分，将其分为右美托咪定敏感组或右美托咪定耐受组，使用Plink软件进行逻辑回归分析发现，rs28399433对右美托咪定镇静敏感性有显著影响[=0.003，OR（95%CI）：0.27（0.11 - 0.65）]。C等位基因携带者比A等位基因携带者对右美托咪定的镇静作用更敏感。rs279847多态性与心率下降程度显著相关。特别是，GG基因型个体心率异常的风险是T等位基因携带者的4倍（OR = 4.32，95%CI：1.96 - 9.50，=0.00027）。rs28399433多态性影响右美托咪定的代谢率，并与右美托咪定镇静作用的易感性相关；rs279847多态性与心率下降程度显著相关。
