Pediatric Adverse Drug Reactions in NASH

NASH 中的儿科药物不良反应

• 批准号: 8209030
• 负责人: Nathan J Cherrington
• 金额: $ 32.19万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-27 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8209030
• 关键词: Acetaminophen; Address; Adolescent; Adult; Adverse event; Adverse reactions; Animal Model; Back; Bile fluid; Biological Markers; Blood; CYP1A2 gene; Child; Childhood; Clinical; Clinical Research; Control Animal; Cytochrome P450; Data; Development; Diagnosis; Disease; Dose; Drug Kinetics; Drug Prescriptions; Enzymes; Fatty Liver; Gene Expression; Genes; Goals; Hepatic; Hepatocyte; Histopathology; Human; Hyperlipidemia; In Vitro; Incidence; Individual; Inflammatory; Insulin Resistance; Liver; Liver diseases; Medicine; Metabolic Biotransformation; Metabolism; NF-E2-related factor 2; Nature; Nuclear; Pathology; Patients; Pharmaceutical Preparations; Phase; Phenotype; Plasma; Play; Prevalence; Procedures; Process; Protein Isoforms; Publications; Reaction; Reporting; Risk; Rodent Model; Role; Sample Size; Sampling; Screening procedure; Staging; Steatohepatitis; Testing; Therapeutic; Up-Regulation; Urine; Variant; base; design; drug metabolism; enzyme substrate; impaired capacity; in vivo; interest; liver biopsy; metabolomics; non-alcoholic fatty liver; nonalcoholic steatohepatitis; obesity in children; public health relevance; response; tool; transcription factor; uptake

DESCRIPTION (provided by applicant): Nonalcoholic fatty liver disease (NAFLD) comprises a spectrum of histopathologies that range from simple steatosis to the more severe steatohepatitis (termed non-alcoholic steatohepatitis or NASH). NAFLD is the most common cause of liver disease in preadolescents and adolescents, and the increased prevalence coincides with the rise in childhood obesity, insulin resistance, and hyperlipidemia. One of the major causes of adverse drug reactions is the inability of the individual patient to handle a standard dose of a prescribed drug. A major goal of individualized medicine is to identify the appropriate dose of a drug that will not elicit an adverse response in that patient. A major factor in determining a safe dose of a drug is the capacity of the patient to metabolize and eliminate that drug from the body. Identifying individuals with an impaired capacity to handle a drug prior to initiating treatment would therefore be instrumental in decreasing the number of adverse drug reactions. For the vast majority of drugs, the liver plays a key role in determining the rate at which drugs are eliminated. Several processes are required for efficient hepatic elimination, including entry into hepatocytes by uptake transporters, Phase I and II biotransformation, and efflux from the liver by drug transporters either into bile or back into the blood. Because the liver plays such a critical role in drug metabolism and disposition, any disease state that disrupts or modifies these functions will alter the fate of numerous drugs within the body. The effect of steatosis and NASH on the expression and activity of the major drug metabolizing enzymes is completely unknown, but could have broad implications in identifying both the patients that are at greater risk of developing adverse drug reactions, and the drugs that are likely to cause adverse events in patients with NASH. Our preliminary results in rodent models and humans with NASH indicate significant changes in the expression of drug metabolizing enzymes and transporters, as well as a functional shift in the disposition of drugs. The two major hypotheses to be addressed are; (1) NASH alters the expression and function of major drug metabolizing enzymes and transporters thereby, increasing the risk of adverse drug reactions in children with NASH and (2) Plasma and/or urine levels of APAP-GLUC can be used as a metabolomic biomarker to identify these patients (with NASH) that may be at risk for adverse drug reactions. Aim 1. Determine whether the in vivo activity of the major CYP enzymes is altered in children with steatosis or NASH. Aim 2. Determine whether the functional disposition of APAP metabolites is altered in patients with fatty liver disease. Aim 3. Determine whether the expression and activity of Phase II and III drug metabolizing enzymes and transporters are altered in human livers diagnosed with steatosis and NASH. PUBLIC HEALTH RELEVANCE: Numerous adverse drug reactions result from the inability of a patient to metabolize and eliminate the standard dose of a drug. Pediatric fatty liver disease may alter the expression of specific drug metabolizing enzymes and transporters which could alter the pharmacokinetics of numerous drugs, thereby increasing the risk of adverse reactions. The current application is designed to determine the effect of NAFLD on the major drug metabolizing enzymes and transporters and whether we can identify patients that are at greater risk of adverse drug reactions before they begin new therapies.

描述（由申请人提供）：非酒精性脂肪肝病（NAFLD）包括一系列组织病理学，范围从简单的脂肪变性到更严重的脂肪性肝炎（称为非酒精性脂肪性肝炎或NASH）。 NAFLD是前肝病和青少年中肝病的最常见原因，而患病率的增加与儿童肥胖症，胰岛素抵抗和高脂血症的增加相吻合。不良药物反应的主要原因之一是单个患者无法处理规定药物的标准剂量。个性化医学的主要目标是确定适当的药物剂量，该药物不会引起该患者的不良反应。确定药物安全剂量的主要因素是患者可以从体内代谢和消除该药物的能力。因此，在开始治疗之前识别患有药物能力受损的人将有助于减少不良药物反应的数量。对于绝大多数药物，肝脏在确定消除药物的速度方面起着关键作用。需要几个过程才能有效消除肝脏消除，包括通过摄取转运蛋白进入肝细胞，I期和II期生物转化，以及药物转运蛋白从肝脏中排出，或者从肝脏中输入胆汁或返回血液。由于肝脏在药物代谢和处置中起着至关重要的作用，因此任何破坏或修改这些功能的疾病状态都会改变体内许多药物的命运。脂肪变性和NASH对主要药物代谢酶的表达和活性的影响是完全未知的，但对于识别出更大风险患不良药物反应的风险的患者可能具有广泛的影响，以及可能在NASH患者中引起不良事件的药物。我们在具有NASH的啮齿动物模型和人类中的初步结果表明，药物代谢酶和转运蛋白的表达发生了显着变化，以及药物处置的功能转移。要解决的两个主要假设是： （1）NASH改变了主要药物代谢酶和转运蛋白的表达和功能，从而增加了NASH儿童和（2）血浆和/或尿液水平APAP-GLUC的不良药物反应的风险，可以用作可代谢性生物标志物，以识别这些患者（含NASH）可能对药物不良反应的风险。 AIM 1。确定脂肪变性或NASH儿童的主要CYP酶的体内活性是否改变。 AIM 2。确定脂肪肝病患者中APAP代谢产物的功能性处理是否改变。 AIM 3。确定II和III期药物代谢酶和转运蛋白的表达和活性是否在被诊断为脂肪变性和NASH的人肝脏中发生了变化。 公共卫生相关性：许多不良药物反应是由于患者无法代谢和消除药物的标准剂量而产生的。小儿脂肪肝病可能会改变特定药物代谢酶和转运蛋白的表达，从而改变许多药物的药代动力学，从而增加了不良反应的风险。当前的应用旨在确定NAFLD对主要药物代谢酶和转运蛋白的影响，以及在开始新疗法之前，我们是否可以识别出对药物反应不良反应的风险更大的患者。