Ontogeny of Phase II Enzymes: SULT, UGT, GST

描述(由申请人提供)：合理药物治疗的目标是以可接受和可预测的方式产生所需的药理反应，同时将不良事件降至最低。就药物分配(即药代动力学)和新陈代谢(即生物转化)而言，儿童不是简单的小成年人。儿童的生物转化途径既不是随着时间的推移而静止的，也不是以线性的方式从胎儿时期到新生儿时期，再到童年、青春期和成年期。为了避免治疗失败或不想要的毒性，必须认识到这些生物转化相对于发育状态的比率。虽然已经研究了生命第一年的第一阶段途径，如CYP2D6和CYP3A4的个体发育，但唯一被类似研究的第二阶段酶是Nat2，它只占第二阶段生物转化的一小部分。APAP是儿科应用最广泛的药物之一。此外，在一次治疗剂量中，不希望出现的副作用很小。APAP通过三种第二相生物转化代谢，即磺基转移酶、谷胱甘肽-S-转移酶和葡萄糖醛酸基转移酶，代表了三种最重要的定性和定量的第二相反应。而新生儿研究表明，相对于SULT活性，它们的绝对II相活性较低，UGT活性较低。到目前为止，还没有活体数据来定义这些重要途径在生命第一年的活动变化。对APAP及其代谢物代谢率的纵向评估将提供这一重要信息。从一般建议中获得的信息也可以应用于通过这些途径代谢的其他重要药物，如齐多夫定、吗啡和劳拉西潘。

DESCRIPTION (provided by applicant): The goal of rational drug therapy is to produce a desired pharmacological response in an acceptable and predictable manner while minimizing undesired events. With respect to drug distribution (i.e. pharmacokinetics) and metabolism (i.e. biotransformation), children are not simply small adults. The biotransformation pathways in children are neither static over time, nor progress in a linear manner from fetal life through neonatal life and then into childhood, adolescence, and adulthood. In order to avoid therapeutic failure or unwanted toxicity, the rate of these biotransformations with respect to developmental state must be appreciated. While the ontogeny of Phase I pathways such as CYP2D6 and CYP3A4 over the first year of life has been studied, the only Phase II enzyme similarly studied is NAT2 which represents only a small proportion of Phase II biotransformations. APAP is one of the most commonly utilized pharmaceutics in pediatrics. Moreover, in a single therapeutic dose, undesired side effects are minimal. APAP is metabolized by three Phase II biotransformations {i.e. sulfotransferase (SULT), glutathione-S-transferase (GST), and glucuronosyltransferases (UGT)}, which represent three of the most important, both qualitative and quantitative, Phase II reactions. While neonatal studies indicate that, they have less absolute phase II activity and reduced UGT activity relative to SULT activity. To date, there is no in vivo data, which define the changes in activity of these important pathways during the first year of life. The longitudinal assessment of the metabolic ratio of APAP and its metabolites will provide this important information. The information gained from general proposal may also be applied to other important drugs metabolized by these pathways such as zidovudine, morphine, and lorazepam.