GLUCURONYL TRANSFERASE ACTIVITY IN THE FETAL PRIMATE

怀孕期间使用的药物种类繁多。尽管如此，我们的知识处置药物对胎儿和胎儿如何代谢各种药物是有限的。葡萄糖醛酸转移酶是一种常见的II期结合系统，在胎儿中被下调，并在出生时被诱导。尽管这种酶在子宫内的活性有限，但我们已经表明，胎儿糖醛酸化药物可以对胎儿药物及其代谢物的浓度产生显著影响。药物浓度降低，代谢物浓度可超过母体。此外。过早诱导这些酶可能会导致更明显的影响。为了预测药物对胎儿可能产生的影响，需要药代动力学模型来估计胎儿的药物和代谢物浓度。本研究以葡萄糖醛酸转移酶为模型，目的是确定胎儿代谢在母体-胎儿整体药代动力学中的作用。我们的总体假设是，胎儿代谢占观察到的药物从胎儿非胎盘清除的显著量。此外，胎儿生命期间葡萄糖醛基转移酶表达的测量将预测胎儿药物和代谢物浓度的可观察变化。我们建议通过对胎儿狒狒的一系列实验来验证这些假设。一种新的药代动力学方法将结合胎儿组织中葡萄糖醛酸转移酶活性的生化测定和表达蛋白（蛋白质免疫分析和稳态mRNA）的定量测量，来定量测定胎儿狒狒中葡萄糖醛酸转移酶代谢物的形成率。我们将量化丁丙诺啡、丙咪嗪、乙胺酚和吗啡在妊娠后期胎儿狒狒体内葡萄糖醛酸盐的形成率，并将其与酶活性的生化测量相关联。我们将量化暴露于苯巴比妥和地塞米松（已知的葡萄糖醛基转移酶诱导剂）后代谢的变化，然后量化这对母体药物给药后胎儿与母体比率的稳定状态的影响。结合孕妇药物治疗的最新进展，迫切需要开发可靠地确定胎儿药物水平的药代动力学模型。这项研究的长期目标是扭转使胎儿成为治疗孤儿的趋势。

A broad pharmocipia of drugs are used in pregnancy. Despite this, our knowledge of the disposition of drug to the fetus and how the fetus metabolizes various drugs is limited. Glucuronyltransferase, a common phase II conjugation system, is down regulated in the fetus and undergoes induction near birth. Despite the limited activity of this enzyme in utero, we have shown that fetal glucuronidation of drugs can have significant effects on fetal concentration of both drugs and their metabolites in the fetus. Drug concentrations are diminished and metabolite concentrations can exceed those in the mother. Furthermore. premature induction of these enzymes could lead to more pronounced effects. To predict the likely effect a drug will have on the fetus, pharmacokinetic models are required to estimate fetal drug and metabolite concentrations. Using glucuronyltransferase as a model, the goal of this proposal, is to establish the role of fetal metabolism in overall maternal-fetal pharmacokinetics. Our overall hypothesis is that fetal metabolism accounts for a significant amount of the observed nonplacental clearance of drug from the fetus. In addition, measures of glucuronyltransferase expression during fetal life will predict the observable changes in fetal drug and metabolite concentrations. We propose to test these hypotheses by a series of experiments in the fetal baboon. A novel pharmacokinetic approach to the quantification of the rate of formation of glucuronide metabolites in the fetal baboon will be combined with biochemical assays of glucuronyltransferase activity and quantitative measures of expressed protein (protein immunoanalysis and steady-state mRNA) in fetal tissues. We will quantify the rate of glucuronide formation of buprenorphine, imipramine, acetominophen, and morphine in the fetal baboon across late gestation and correlate this with biochemical measures of enzyme-activity. We will quantify the change in metabolism following exposure to phenobarbital and dexamethasone, known inducers of glucuronyltransferase, and then quantify the effect this has on steady-state fetal-to-maternal ratios following maternal drug administration. In conjunction with recent advances in pharmacologic therapy for pregnant women, there is a pressing need for developing pharmacokinetic models which reliably define drug levels in the fetus. The long-term goal of this research is to reverse a trend which left the fetus as a therapeutic orphan.