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期望的药理反应，同时尽量减少不希望发生的事件。在药物分布（即药代动力学）和代谢（即生物转化）方面，儿童不仅仅是小个子成年人。随着时间的推移，儿童的生物转化途径既不是静态的，也不是从胎儿到新生儿再到儿童、青春期和成年期的线性进展。为了避免治疗失败或不必要的毒性，这些生物转化的速度相对于发育状态必须得到重视。虽然已经研究了CYP2D6和CYP3A4等I期途径在生命第一年的个体发生，但唯一类似研究的II期酶是NAT2，它只占II期生物转化的一小部分。APAP是儿科最常用的药物之一。此外，在单次治疗剂量下，不良副作用最小。APAP通过三个II期生物转化代谢{即：硫转移酶（SULT），谷胱甘肽- s转移酶（GST）和葡萄糖醛酸转移酶（UGT）}，它们代表了定性和定量上最重要的三种II期反应。而新生儿研究表明，相对于SULT活性，它们具有较低的绝对II期活性和较低的UGT活性。到目前为止，还没有体内数据来确定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、吗啡和劳拉西泮。

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.