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: 9244047
• 负责人: XIAO-BO ZHONG
• 金额: $ 29.93万
• 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/9244047
• 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; Early treatment; Enzymes; Epigenetic Process; Exposure to; Funding Opportunities; Gene Expression; Gene Expression Alteration; Gene Mutation; Goals; Growth; Hepatotoxicity; Human; Infant; Knowledge; Life; Ligands; Liver; Midazolam; Mus; Nuclear Receptors; Omeprazole; 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; epigenetic memory; liver injury; neonate; outcome prediction; 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（应用程序提供）：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“药代动力学在早期发展中对药物暴露涉及的药代动力学涉及基因的短期或长期变化问题的紧迫性”。医师使用药物治疗新生儿和婴儿中的各种疾病。但是，当前的临床实践并未考虑到对患者在成年后对患者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早期药物暴露对药物代谢，治疗有效性以及药物诱导毒性的潜力的后果（短期或长期）。这项研究的目的是了解早期药物暴露对药物代谢，治疗有效性和药物诱导的毒性的短期或长期影响。根据先前的出版物和我们的初步数据，我们形成了一个中心假设：“早期生命暴露于具有激活核受体能力的药物可能会导致直接（短期）或持续（长期）或持久（长期）表达和功能的变化和某些药物代谢酶的酶的促进性的影响，从而对药物的效率进行了差异，这是对药物的效率的影响。特定年龄的一定剂量可以改变肝脏的表观遗传记忆。”我们组成了一个调查员团队，拥有必要的专家来完成拟议的工作。我们将在早期使用苯巴比妥，奥美拉唑和咪达唑仑用于治疗效率，以及对乙酰氨基酚的肝毒性。我们将专注于P450（例如CYP2B，CYP2C和CYP3A）作为我们的目标药物代谢酶和小鼠作为我们的动物模型，以检查以下特定目的中的中心假设。 AIM 1将确定药物暴露在早期生命中对药物代谢的短期或长期影响。 AIM 2将确定早期终生药物暴露​​对治疗的短期或长期影响。 AIM 3将确定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，我们将填补有关早期终生对药物代谢的短期或长期影响的知识差距。这种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反应和对药物诱导的毒性的敏感性在整个生命中的敏感性的结果。