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.在发育进程中，药物代谢酶的表达会发生深刻改变，这将对新生儿及幼儿的药物疗效与不良事件发生风险产生影响。基于当前的研究认知，可将肝脏药物代谢酶按其发育轨迹划分为三类。第1类与第3类酶的围产期变化的时间跨度在不同酶之间差异显著；但针对某一特定酶而言，其围产期变化的时机存在明显的个体间差异，由此形成了高变异性窗口。遗传变异显然会影响儿童的药物处置过程，不过发育因素往往会主导药物遗传因素的作用。因此，将药物基因组学应用于提升儿科药物安全性时，面临的一项核心挑战是明确：在何种年龄阶段，成人中已鉴定出的功能遗传变异会成为儿童体内酶表达的主要决定因素。有关药物代谢酶个体发生的发育与遗传数据，以及其他影响药物处置的生理因素的年龄依赖性变化，均可整合至生理药代动力学模型中。此类模型已被证实可有效预测特定年龄下预期的代谢能力范围。