GLUCURONYL TRANSFERASE ACTIVITY IN THE FETAL PRIMATE

灵长类胎儿的葡萄糖醛酸转移酶活性

• 批准号: 6797937
• 负责人: MARIANNE GARLAND
• 金额: $ 42.63万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-29 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6797937
• 关键词: acetaminophen; baboons; biological models; buprenorphine; dexamethasone; embryo /fetus; embryo /fetus pharmacology; enzyme activity; glucuronosyltransferase; imipramine; morphine; pharmacokinetics; phenobarbital

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.

怀孕期间使用的药物种类繁多。 尽管如此，我们对药物在胎儿体内的分布以及胎儿如何代谢各种药物的知识仍然有限。 葡萄糖醛酸转移酶是一种常见的II相结合系统，在胎儿中下调，并在接近出生时进行诱导。 尽管这种酶在子宫内的活性有限，但我们已经证明，药物的胎儿葡萄糖醛酸化可能对胎儿中两种药物及其代谢产物的胎儿浓度产生显著影响。药物浓度降低，代谢物浓度可能超过母体。此外。这些酶的过早诱导可能导致更显著的效果。为了预测药物对胎儿的可能影响，需要药代动力学模型来估计胎儿药物和代谢物浓度。使用葡萄糖醛酸转移酶作为模型，本提案的目的是确定胎儿代谢在总体母胎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胎儿非胎盘药物清除的重要部分。此外，胎儿期葡萄糖醛酸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。我们建议通过在狒狒胎儿身上进行一系列实验来检验这些假设。将采用一种新的药代动力学方法定量测定胎儿狒狒中葡萄糖醛酸代谢产物的形成速率，并结合葡萄糖醛酸转移酶活性的生化测定和胎儿组织中表达蛋白的定量测定（蛋白免疫分析和稳态mRNA）。我们将定量丁丙诺啡、丙咪嗪、对乙酰氨基酚和吗啡在妊娠晚期的狒狒胎儿中的葡糖苷酸形成率，并将其与酶活性的生化指标相关联。我们将量化暴露于苯巴比妥和地塞米松（已知的葡萄糖醛酸转移酶诱导剂）后的代谢变化，然后量化母体给药后对稳态胎母比的影响。结合孕妇药物治疗的最新进展，迫切需要开发可靠定义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胎儿作为治疗孤儿的趋势。