Hines Ronald N
Department of Pediatrics, Medical College of Wisconsin, and Children's Research Institute, Children's Hospital and Health Systems, Milwaukee, WI 53226-4801, USA.
Pharmacol Ther. 2008 May;118(2):250-67. doi: 10.1016/j.pharmthera.2008.02.005. Epub 2008 Mar 5.
Profound changes in drug metabolizing enzyme (DME) expression occurs during development that impacts the risk of adverse drug events in the fetus and child. A review of our current knowledge suggests individual hepatic DME ontogeny can be categorized into one of three groups. Some enzymes, e.g., CYP3A7, are expressed at their highest level during the first trimester and either remain at high concentrations or decrease during gestation, but are silenced or expressed at low levels within one to two years after birth. SULT1A1 is an example of the second group of DME. These enzymes are expressed at relatively constant levels throughout gestation and minimal changes are observed postnatally. ADH1C is typical of the third DME group that are not expressed or are expressed at low levels in the fetus, usually during the second or third trimester. Substantial increases in enzyme levels are observed within the first one to two years after birth. Combined with our knowledge of other physiological factors during early life stages, knowledge regarding DME ontogeny has permitted the development of robust physiological based pharmacokinetic models and an improved capability to predict drug disposition in pediatric patients. This review will provide an overview of DME developmental expression patterns and discuss some implications of the data with regards to drug therapy. Common themes emerging from our current knowledge also will be discussed. Finally, the review will highlight gaps in knowledge that will be important to advance this field.
药物代谢酶（DME）表达在发育过程中发生深刻变化，这会影响胎儿和儿童发生药物不良事件的风险。对我们现有知识的回顾表明，个体肝脏DME的个体发生可分为三组中的一组。一些酶，例如CYP3A7，在孕早期表达水平最高，在妊娠期间要么保持高浓度，要么下降，但在出生后一到两年内会沉默或低水平表达。SULT1A1是第二组DME的一个例子。这些酶在整个妊娠期表达水平相对恒定，出生后变化很小。ADH1C是第三组DME的典型代表，在胎儿期通常在孕中期或晚期不表达或低水平表达。在出生后的头一到两年内观察到酶水平大幅增加。结合我们对生命早期其他生理因素的了解，有关DME个体发生的知识已促使建立强大的基于生理的药代动力学模型，并提高了预测儿科患者药物处置的能力。本综述将概述DME的发育表达模式，并讨论这些数据对药物治疗的一些影响。还将讨论从我们现有知识中出现的共同主题。最后，本综述将突出知识空白，这些空白对于推动该领域发展至关重要。
