Pediatric Adverse Drug Reactions in NASH

NASH 中的儿科药物不良反应

• 批准号: 8598918
• 负责人: Nathan J Cherrington
• 金额: $ 31.29万
• 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/8598918
• 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; 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; screening; 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.

描述（由申请人提供）：非酒精性脂肪性肝病（NAFLD）包括一系列组织病理学，范围从单纯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是青春期前和青少年肝脏疾病的最常见原因，患病率的增加与儿童肥胖、胰岛素抵抗和高脂血症的增加相吻合。药物不良反应的主要原因之一是患者个人无法处理处方药物的标准剂量。个体化治疗的一个主要目标是确定不会引起患者不良反应的适当剂量的药物。决定药物安全剂量的一个主要因素是病人代谢和排出体内药物的能力。因此，在开始治疗之前识别出处理药物能力受损的个体将有助于减少药物不良反应的数量。对于绝大多数药物来说，肝脏在决定药物被清除的速度方面起着关键作用。有效的肝脏清除需要几个过程，包括通过摄取转运体进入肝细胞，I期和II期生物转化，以及药物转运体从肝脏流出进入胆汁或返回血液。由于肝脏在药物代谢和处置中起着至关重要的作用，任何破坏或改变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，但在识别发生药物不良反应风险较大的患者以及可能导致NASH患者不良事件的药物方面可能具有广泛的意义。我们在啮齿动物模型和NASH患者身上的初步结果表明，药物代谢酶和转运蛋白的表达发生了显著变化，药物处置也发生了功能转变。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患儿发生药物不良反应的风险；(2)血浆和/或尿液中APAP-GLUC水平可作为代谢组学生物标志物，用于识别可能存在药物不良反应风险的NASH患者。目的1。确定脂肪变性或NASH患儿体内主要CYP酶的活性是否发生改变。目标2。确定脂肪肝患者APAP代谢物的功能配置是否改变。目标3。确定II期和III期药物代谢酶和转运体在诊断为脂肪变性和NASH的人肝脏中的表达和活性是否改变。