Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, OH, USA.
Pharmacogenomics. 2013 Jul;14(10):1141-51. doi: 10.2217/pgs.13.94.
Large interindividual variability in morphine disposition could contribute to unpredictable variability in morphine analgesia and adverse events. Caucasian children have more adverse effects and slower morphine clearance than African-American children. To study variations in intravenous morphine pharmacokinetics in children, we examined the influence of genetic polymorphisms in OCT1.
In 146 children undergoing adenotonsillectomy, 146 concentration-time profiles (2-4 measurements per patient) were available. Population pharmacokinetic analysis characterized the profiles in NONMEM(®) and tested OCT1 variants as covariates.
Allometrically scaled post hoc Bayesian morphine clearance in homozygotes of loss-of-function OCT1 variants (n = 9, OCT1*2-*5/*2-5) was significantly lower (20%) than in wild-type (n = 85, OCT11/1) and heterozygotes (n = 52, OCT11/*2-*5; p < 0.05).
Besides bodyweight, OCT1 genotypes play a significant role in intravenous morphine pharmacokinetics. Relatively high allelic frequencies of defective OCT1 variants among Caucasians may explain their lower morphine clearance and possibly higher frequencies of adverse events compared with African-American children. Original submitted 21 December 2012; Revision submitted 7 May 2013.
吗啡处置的个体间差异很大，可能导致吗啡镇痛和不良反应的不可预测性变化。与非裔美国儿童相比，白种儿童的不良反应更多，吗啡清除率更慢。为了研究儿童静脉内吗啡药代动力学的变化，我们研究了 OCT1 基因多态性的影响。
在 146 例接受腺样体扁桃体切除术的儿童中，有 146 例（每个患者 2-4 次测量）获得了浓度-时间曲线。群体药代动力学分析在 NONMEM（R）中对曲线进行了特征描述，并将 OCT1 变体作为协变量进行了测试。
在功能丧失 OCT1 变体（n = 9，OCT1*2-*5/*2-5）纯合子中，按比例缩放的事后贝叶斯吗啡清除率明显低于野生型（n = 85，OCT11/1）和杂合子（n = 52，OCT11/*2-*5；p < 0.05）。
除了体重之外，OCT1 基因型在静脉内吗啡药代动力学中也起着重要作用。在白种人中，缺陷 OCT1 变体的等位基因频率相对较高，这可能解释了他们的吗啡清除率较低，以及与非裔美国儿童相比不良反应发生率较高的原因。
