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

 描述(由申请人提供)：NIH的资助机会“PAR-13-306：发育药理学和毒理学：个体遗传学的作用”强调了解决“参与药物动力学的基因的短期或长期变化以响应早期开发中的药物暴露”这一问题的紧迫性。医生使用药物来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成年患者代谢药物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接触药物对药物代谢、治疗效果和潜在药物毒性的后果(短期或长期)。这项研究的目的是了解生命早期接触药物对药物代谢、治疗效果和药物毒性的短期或长期影响。根据以前的文献和我们的初步数据，我们形成了一个中心假说，即早期接触具有激活核受体能力的药物可导致某些药物代谢酶的表达和功能立即(短期)或持久(长期)改变，进一步导致治疗效果和对其他药物毒性敏感性的改变。这种影响取决于在特定年龄使用一定剂量的药物暴露改变肝脏表观遗传记忆的能力。我们已成立了一支由专家组成的调查小组，以完成拟议的工作。我们将在生命早期使用苯巴比妥治疗药物暴露，使用奥美拉唑和咪达唑仑治疗疗效，使用对乙酰氨基酚治疗肝毒性。我们将以P450(如Cyp2b、Cyp2c和CyP3a)为目标药物代谢酶，以小鼠为动物模型，在以下特定目标中检验中心假设。目标1将确定生命早期接触药物对药物代谢的短期或长期影响。目标2将确定生命早期接触药物对治疗效果的短期或长期影响。目的3将确定生命早期接触药物对药物所致肝毒性的短期或长期影响。在完成具体目标后，我们将填补关于生命早期接触药物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更好地预测早期药物暴露对药物反应和终生药物毒性敏感性的影响至关重要。

 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.