Balyan Rajiv, Zhang Xue, Chidambaran Vidya, Martin Lisa J, Mizuno Tomoyuki, Fukuda Tsuyoshi, Vinks Alexander A, Sadhasivam Senthilkumar
Department of Anesthesia, College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA.
Division of Clinical Pharmacology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Pharmacogenomics. 2017 May;18(7):621-629. doi: 10.2217/pgs-2017-0002. Epub 2017 May 4.
Large interindividual variability in morphine pharmacokinetics (PK) could contribute to variability in morphine analgesia and adverse events. Respiratory depression (RD) and postoperative nausea and vomiting (PONV) are significant adverse drug response of intravenous morphine in the perioperative setting limiting its efficacy in achieving adequate surgical pain relief. OCT1 is a transporter in the liver that transports morphine from the bloodstream into hepatocytes. Earlier we reported association of genetic polymorphisms in OCT1 with morphine PK, and lower morphine clearance in Caucasian children as compared with African-American (AA) children. The aim of this study is to identify the association between common OCT1 genotypes affecting morphine's PK and clinically important postoperative morphine-related adverse outcomes.
After obtaining institutional review board (IRB) approval and informed consents, 311 children ages 6-15 years, American Society of Anesthesiologists' physical status 1 or 2 scheduled for tonsillectomy who received standard anesthetic, surgical and postoperative care were recruited. Clinical data collected included postoperative pain scores, total opioid use, incidence of PONV and RD. Four nonsynonymous SNPs of the OCT1 gene (rs12208357, rs34130495, rs72552763 and rs34059508) in each patient were genotyped using commercially available TaqMan assays. We investigated the genetic association of OCT1 with incidences of postoperative RD and PONV.
Caucasian and AA children differed significantly in the incidence of obstructive sleep apnea (p < 0.001) and total morphine use (p = 0.028). There were incidences of prolonged post anesthesia care unit stay in 7% of Caucasian children, while no such incidences were observed for AA children (p = 0.05). OCT1 polymorphism rs12208357 was associated with high incidences of PONV and PONV leading to prolonged post anesthesia care unit stay (p < 0.05). A significant association was also found between rs72552763 GAT deletion and high incidence of RD (p = 0.007).
Children with certain OCT1 genotypes are associated with higher risk for RD and PONV following morphine administration leading to prolonged hospital stay. The OCT1 transporters' effects on morphine's PK could explain this association.
吗啡药代动力学（PK）存在较大的个体间差异，这可能导致吗啡镇痛效果和不良事件的差异。呼吸抑制（RD）和术后恶心呕吐（PONV）是围手术期静脉注射吗啡的重要药物不良反应，限制了其在实现充分手术疼痛缓解方面的疗效。有机阳离子转运体1（OCT1）是肝脏中的一种转运蛋白，可将吗啡从血液转运到肝细胞中。我们之前报道过OCT1基因多态性与吗啡PK的关联，以及与非裔美国（AA）儿童相比，白种儿童吗啡清除率较低。本研究的目的是确定影响吗啡PK的常见OCT1基因型与临床上重要的术后吗啡相关不良结局之间的关联。
在获得机构审查委员会（IRB）批准并获得知情同意后，招募了311名6至15岁、美国麻醉医师协会身体状况为1或2、计划接受扁桃体切除术且接受标准麻醉、手术和术后护理的儿童。收集的临床数据包括术后疼痛评分、总阿片类药物使用量、PONV和RD的发生率。使用市售的TaqMan分析对每位患者OCT1基因的四个非同义单核苷酸多态性（SNP，rs12208357、rs34130495、rs72552763和rs34059508）进行基因分型。我们研究了OCT1与术后RD和PONV发生率之间的遗传关联。
白种儿童和AA儿童在阻塞性睡眠呼吸暂停发生率（p < 0.001）和总吗啡使用量（p = 0.028）方面存在显著差异。7%的白种儿童出现麻醉后监护病房停留时间延长的情况，而AA儿童未观察到此类情况（p = 0.05）。OCT1多态性rs12208357与PONV的高发生率以及导致麻醉后监护病房停留时间延长的PONV相关（p < 0.05）。还发现rs72552763 GAT缺失与RD的高发生率之间存在显著关联（p = （此处原文可能有误，推测为0.007））。
具有某些OCT1基因型的儿童在使用吗啡后发生RD和PONV的风险较高，导致住院时间延长。OCT1转运蛋白对吗啡PK的影响可以解释这种关联。
