Short- or long-term impacts of drug exposure at early life on drug metabolism, therapeutic efficacy, and drug-induced toxicity

生命早期药物暴露对药物代谢、治疗效果和药物引起的毒性的短期或长期影响

• 批准号: 9077520
• 负责人: XIAO-BO ZHONG
• 金额: $ 31.4万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9077520
• 关键词: Acetaminophen; Address; Adult; Age; Animal Model; Basic Science; ChIP-seq; Clinical Research; Cytochrome P450; Data; Development; Disease; Dose; Drug Exposure; Drug Kinetics; Drug Metabolism Alteration; Drug Targeting; Drug usage; Enzymes; Epigenetic Process; Exposure to; Funding Opportunities; Gene Expression; Gene Expression Alteration; Gene Expression Profile; Gene Mutation; Goals; Growth; Hepatotoxicity; Human; Infant; Knowledge; Life; Ligands; Liver; Midazolam; Mus; Nuclear Receptors; Omeprazole; Outcome; Patients; Pharmaceutical Preparations; Pharmacology and Toxicology; Pharmacotherapy; Phenobarbital; Physicians; Proteomics; Publications; Research Personnel; Risk; Role; Testing; Toxic effect; Treatment Efficacy; United States National Institutes of Health; Work; base; clinical practice; constitutive androstane receptor; drug metabolism; drug testing; early life exposure; efficacy testing; epigenetic memory; liver injury; neonate; postnatal; public health relevance; response; transcriptome sequencing

 DESCRIPTION (provided by applicant): The NIH Funding Opportunity "PAR-13-306: Developmental Pharmacology and Toxicology: Role of Ontogeny" emphasizes the urgency of addressing the issue of "short- or long-term alterations of genes involved in pharmacokinetics in response to drug exposure in early development". Physicians use drugs to treat various diseases in neonates and infants. However, the current clinical practices have not considered the potential short- or long-term consequences on the patient's ability to metabolize drugs during adulthood who have received drug treatment early in life. A major reason is the lack of basic research to understand the consequences (short- or long-term) that drug exposure in early life has on drug metabolism, therapeutic efficacy, and potential for drug-induced toxicity. The goal in this study is to understand the short- or long-term impacts of drug exposure at early life on drug metabolism, therapeutic efficacy, and drug-induced toxicity. Based on the previous publications and our preliminary data, we have formed a central hypothesis that "early life exposure to drugs that have the ability to activate nuclear receptors can result in either immediate (short-term) or persistent (long-term) alterations of expression and functions of certain drug metabolizing enzymes, further leading to alterations in therapeutic efficacy and sensitivity to toxicity of other drugs. This effect is dependent on the ability of the drug exposur with a certain dose at a specific age to alter epigenetic memory in liver." We have formed an investigator team with experts necessary to accomplish the proposed works. We will use phenobarbital for drug exposure at early life, omeprazole and midazolam for therapeutic efficacy, and acetaminophen for hepatotoxicity. We will focus on P450s (such as Cyp2b, Cyp2c, and Cyp3a) as our target drug metabolizing enzymes and the mouse as our animal model to examine the central hypothesis in the following specific aims. Aim 1 will determine the short- or long-term impacts of drug exposure at early life on drug metabolism. Aim 2 will determine the short- or long-term impacts of drug exposure at early life on therapeutic efficacy. Aim 3 will determine the short- or long-term impacts of drug exposure at early life on drug-induced hepatotoxicity. After completion of the specific aims, we will fill the knowledge gaps on the short or long-term impacts of drug exposure at early life on drug metabolism. Such knowledge is critical for developmental pharmacology and toxicology to better predict outcomes of drug exposure at early ages on drug responses and sensitivity to drug-induced toxicity throughout the lifetime.

 描述（由申请人提供）：NIH资助机会“PAR-13-306：发育药理学和毒理学：个体发育的作用”强调了解决“早期发育中药物暴露引起的药代动力学相关基因的短期或长期改变”问题的紧迫性。医生使用药物治疗新生儿和婴儿的各种疾病。然而，目前的临床实践没有考虑到对在生命早期接受药物治疗的患者在成年期间代谢药物的能力的潜在短期或长期后果。一个主要原因是缺乏基础研究来了解生命早期药物暴露对药物代谢、治疗效果和药物诱导毒性的潜在影响（短期或长期）。本研究的目的是了解生命早期药物暴露对药物代谢、疗效和药物诱导毒性的短期或长期影响。基于以前的出版物和我们的初步数据，我们已经形成了一个中心假设，即“生命早期暴露于具有激活核受体能力的药物可能导致某些药物代谢酶的表达和功能的立即（短期）或持续（长期）改变，进一步导致其他药物的疗效和毒性敏感性的改变。这种效果取决于药物在特定年龄以一定剂量改变肝脏中的表观遗传记忆的能力。“我们已成立一个由专家组成的调查小组，以完成拟议的工程。我们将使用苯巴比妥用于早期药物暴露，奥美拉唑和咪达唑仑用于治疗效果，对乙酰氨基酚用于肝毒性。我们将重点关注P450（如Cyp 2b，Cyp 2c和Cyp 3a）作为我们的目标药物代谢酶和小鼠作为我们的动物模型，以检验以下具体目标的中心假设。目的1将确定药物暴露在药物代谢的早期生命的短期或长期影响。目标2将确定早期药物暴露对治疗效果的短期或长期影响。目的3将确定在生命早期药物暴露对药物诱导的肝毒性的短期或长期影响。在完成具体目标后，我们将填补生命早期药物暴露对药物代谢的短期或长期影响的知识空白。这些知识对于发育药理学和毒理学至关重要，可以更好地预测早期药物暴露对药物反应的影响以及整个生命周期对药物诱导毒性的敏感性。