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 是青春期前和青少年肝病的最常见原因，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一致。药物不良反应的主要原因之一是个体患者无法处理标准剂量的处方药物。个体化医疗的一个主要目标是确定不会引起患者不良反应的适当药物剂量。确定药物安全剂量的一个主要因素是患者代谢和清除体内药物的能力。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，肝脏在决定药物消除速度方面起着关键作用。有效的肝脏消除需要几个过程，包括通过摄取转运蛋白进入肝细胞、第一阶段和第二阶段生物转化，以及通过药物转运蛋白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完全未知，但可能对识别发生药物不良反应风险较高的患者以及可能导致药物不良反应的药物具有广泛的影响。 NASH 患者的不良事件。我们在患有 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变。要解决的两个主要假设是： (1) NASH 改变主要药物代谢酶和转运蛋白的表达和功能，从而增加 NASH 儿童药物不良反应的风险；(2) 血浆和/或尿液中 APAP-GLUC 水平可作为代谢组生物标志物识别这些可能存在药物不良反应风险的患者（NASH）。目标 1. 确定患有脂肪变性或 NASH 的儿童中主要 CYP 酶的体内活性是否发生改变。目标 2. 确定脂肪肝患者中 APAP 代谢物的功能配置是否发生改变。目标 3. 确定诊断患有脂肪变性和 NASH 的人类肝脏中 II 期和 III 期药物代谢酶和转运蛋白的表达和活性是否发生改变。