Pediatric Adverse Drug Reactions in NASH

描述（由申请方提供）：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。个体化用药的一个主要目标是确定不会引起患者不良反应的药物的适当剂量。确定药物安全剂量的一个主要因素是患者代谢和消除体内药物的能力。因此，在开始治疗前识别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，肝脏在决定药物消除速率方面发挥着关键作用。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、I期和II期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是完全未知的，但在确定发生药物不良反应的风险更大的患者和可能导致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著变化，药物处置也发生了功能性转变。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儿童中药物不良反应的风险;（2）APAP-GLUC的血浆和/或尿液水平可用作代谢组学生物标志物，以识别可能存在药物不良反应风险的这些患者（NASH患者）。目标1.确定患有脂肪变性或NASH的儿童体内的主要转氨酶活性是否改变。目标2.确定脂肪肝患者APAP代谢物的功能分布是否改变。目标3.确定诊断为脂肪变性和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。 公共卫生相关性：许多药物不良反应是由于患者不能代谢和消除标准剂量的药物而引起的。儿童脂肪肝可能改变特定药物代谢酶和转运蛋白的表达，这可能改变许多药物的药代动力学，从而增加不良反应的风险。目前的申请旨在确定NAFLD对主要药物代谢酶和转运蛋白的影响，以及我们是否可以在患者开始新治疗之前识别出药物不良反应风险更高的患者。

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.