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.发育过程中，药物代谢酶（drug metabolizing enzyme）的表达会发生显著变化，这会影响新生儿（neonate）及幼儿的药物疗效与不良事件发生风险。基于现有研究综述，可根据发育轨迹（developmental trajectories）将各类肝脏药物代谢酶（hepatic drug metabolizing enzyme）划分为三类。第1类与第3类酶的围产期（perinatal）变化的时间窗口，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点存在显著的个体间差异（interindividual variation），由此形成高变异性窗口。遗传变异显然会影响儿童的药物处置（drug disposition）过程，但发育因素往往会主导药物遗传学（pharmacogenetic）因素的影响。因此，利用药物基因组学（pharmacogenomics）提升儿科药物安全性的一大核心挑战，在于明确：在何种年龄阶段，成人中发现的功能遗传变异（functional genetic variants）会成为儿童药物代谢酶表达的主要调控因素。可将药物代谢酶个体发生（ontogeny）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，整合至基于生理的药代动力学模型（physiologically-based pharmacokinetic models）当中。此类模型已被证实可有效预测特定年龄阶段的预期代谢能力范围。