Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
J Clin Pharmacol. 2020 Aug;60(8):992-998. doi: 10.1002/jcph.1592. Epub 2020 Feb 24.
We have previously reported the influences of OCT1 ontogeny and genetic variation on morphine clearance in neonatal and pediatric patients. In the latter study, plasma morphine-glucuronide levels correlated with patient genotype for the rs4793665 single-nucleotide polymorphism (SNP) at the locus of MRP3, an efflux transporter of morphine glucuronides between hepatocytes and circulating blood. The link between MRP3 activity and overall morphine clearance has not been thoroughly investigated however, and the developmental profile of hepatic MRP3 protein expression remains thinly defined between neonates and adults. In the current study, previously determined morphine clearance values for neonatal (24-58 weeks postmenstrual age, N = 57) and pediatric (5-16 years, n = 85) patients were reanalyzed for correlation to the SNP genotype of patient rs4793665. Among OCT1 wild-type patients, pediatric morphine clearance showed a significant decreasing trend by MRP3 genotypes in the order of CC > CT > TT (P = .014), whereas for neonates, an identical but nonsignificant trend was observed. Pharmacogenetic differences in MRP3 and OCT1 ontogeny were evaluated by Western blot of hepatic membrane fractions from 50 subjects aged 1 day postnatal to 33 years old. Hepatic MRP3 protein level did not vary by rs4793665 genotype, and followed an atypical developmental pattern of increase up to 1-2 years of age, thereafter decreasing during preadolescence before increasing again to adult levels at maturity (17-33 years). By comparison, OCT1 expression was significantly decreased in OCT1 *1/*3 genotyped patients older than 1 year and followed a trajectory consistent with prior studies. Our results suggest that consideration of MRP3 pharmacogenetics and ontogeny may aid in identifying pediatric patients having different/atypical morphine requirements.
我们之前曾报道过 OCT1 的发育和遗传变异对新生儿和儿科患者吗啡清除率的影响。在后一项研究中，血浆吗啡-葡萄糖醛酸水平与 MRP3 基因座上的 rs4793665 单核苷酸多态性（SNP）的患者基因型相关，MRP3 是葡萄糖醛酸吗啡在肝细胞和循环血液之间的流出转运体。然而，MRP3 活性与整体吗啡清除率之间的联系尚未得到彻底研究，并且肝 MRP3 蛋白表达的发育特征在新生儿和成人之间仍未得到充分定义。在本研究中，我们重新分析了先前确定的新生儿（胎龄 24-58 周，N=57）和儿科（5-16 岁，n=85）患者的吗啡清除率值，以与患者 rs4793665 的 SNP 基因型相关。在 OCT1 野生型患者中，儿科吗啡清除率按 MRP3 基因型呈显著下降趋势，顺序为 CC>CT>TT（P=0.014），而对于新生儿，观察到相同但无统计学意义的趋势。通过对 50 名年龄从出生后 1 天到 33 岁的受试者的肝膜部分进行 Western blot 分析，评估了 MRP3 和 OCT1 发育的药物遗传学差异。肝 MRP3 蛋白水平与 rs4793665 基因型无关，呈不典型的发育模式，在 1-2 岁时增加，然后在青春期前下降，然后在成熟时（17-33 岁）再次增加到成人水平。相比之下，OCT1 表达在年龄大于 1 岁的 OCT1*1/*3 基因型患者中显著降低，并且遵循与先前研究一致的轨迹。我们的研究结果表明，考虑 MRP3 药物遗传学和发育可能有助于识别具有不同/异常吗啡需求的儿科患者。
