Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
CPT Pharmacometrics Syst Pharmacol. 2018 Jul;7(7):464-473. doi: 10.1002/psp4.12306. Epub 2018 Jun 19.
Morphine has large pharmacokinetic variability, which is further complicated by developmental changes in neonates and small infants. The impacts of organic cation transporter 1 (OCT1) genotype and changes in blood-flow on morphine clearance (CL) were previously demonstrated in children, whereas changes in UDP-glucuronosyltransferase 2B7 (UGT2B7) activity showed a small effect. This study, targeting neonates and small infants, was designed to assess the influence of developmental changes in OCT1 and UGT2B7 protein expression and modified blood-flow on morphine CL using physiologically based pharmacokinetic (PBPK) modeling. The implementation of these three age-dependent factors into the pediatric system platform resulted in reasonable prediction for an age-dependent increase in morphine CL in these populations. Sensitivity of morphine CL to changes in cardiac output increased with age up to 3 years, whereas sensitivity to changes in UGT2B7 activity decreased. This study suggests that morphine exhibits age-dependent extraction, likely due to the developmental increase in OCT1 and UGT2B7 protein expression/activity and hepatic blood-flow.
吗啡具有较大的药代动力学变异性，新生儿和小婴儿的发育变化进一步使其复杂化。先前在儿童中已经证明了有机阳离子转运蛋白 1（OCT1）基因型和血流变化对吗啡清除率（CL）的影响，而 UDP-葡萄糖醛酸基转移酶 2B7（UGT2B7）活性的变化则显示出较小的影响。本研究针对新生儿和小婴儿，旨在使用基于生理学的药代动力学（PBPK）模型评估 OCT1 和 UGT2B7 蛋白表达和改良血流的发育变化对吗啡 CL 的影响。将这三个年龄相关因素纳入儿科系统平台中，可合理预测这些人群中吗啡 CL 的年龄依赖性增加。对心输出量变化的敏感性随着年龄的增长而增加，直至 3 岁，而对 UGT2B7 活性变化的敏感性则降低。本研究表明，吗啡表现出年龄依赖性提取，可能是由于 OCT1 和 UGT2B7 蛋白表达/活性和肝血流量的发育增加所致。
