Data from: Developmental expression of drug metabolizing enzymes: impact on disposition in neonates and young children

Profound changes in drug metabolizing enzyme expression occurs during development that impacts drug efficacy and the risk of adverse events in the neonate and young child. A review of our current knowledge suggests individual hepatic drug metabolizing enzymes can be categorized into one of three classes based on developmental trajectories. The time frame for the perinatal changes observed for both Class 1 and Class 3 enzymes varies considerably between different enzymes. However, for a given enzyme, significant interindividual variation is observed in the timing of the perinatal changes, creating windows of hypervariability. Genetic variation clearly impacts drug disposition in children. However, developmental factors can dominate pharmacogenetic factors. Thus, a major challenge in applying pharmacogenomics to improve pediatric drug safety is determining at what age functional genetic variants identified in adults become a major determinant of expression in children. Developmental and genetic data on drug metabolizing enzyme ontogeny, as well as age-dependent changes in other physiological factors impacting drug disposition, can be integrated into physiologically-based pharmacokinetic models. Such models have proven useful in predicting the range of expected metabolic capacities at a given age.

药物代谢酶（drug metabolizing enzyme）的表达在发育进程中会发生显著变化，此类变化会影响新生儿与幼儿的药物疗效，并提升不良事件的发生风险。现有研究综述显示，可根据发育轨迹将各类肝脏药物代谢酶（hepatic drug metabolizing enzyme）分为三类。1类与3类酶的围产期变化时间窗，在不同酶之间存在显著差异。但对于特定酶而言，其围产期变化的时间存在显著的个体间差异，进而形成高变异性窗口期。遗传变异显然会影响儿童的药物处置（drug disposition）。然而，发育因素往往会凌驾于药物遗传药理学（pharmacogenetic）因素之上。因此，利用药物基因组学（pharmacogenomics）提升儿科药物安全性所面临的核心挑战，在于确定成年人群中发现的功能性遗传变异，在儿童群体中何时会成为药物代谢酶表达的主要调控因素。我们可将药物代谢酶个体发生（drug metabolizing enzyme ontogeny）相关的发育与遗传数据，以及其他影响药物处置的年龄依赖性生理因素变化，整合至基于生理学的药代动力学模型（physiologically-based pharmacokinetic models）中。此类模型已被证实可用于预测特定年龄阶段机体预期的代谢能力范围。