Pediatric Adverse Drug Reactions in NASH

描述(申请人提供)：非酒精性脂肪性肝病(NAFLD)包括一系列的组织病理学，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)。非酒精性脂肪肝是青少年前和青少年中最常见的肝病原因，发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。药物不良反应的主要原因之一是患者个人无法处理标准剂量的处方药。个体化用药的一个主要目标是确定不会在患者身上引起不良反应的适当剂量的药物。决定一种药物安全剂量的一个主要因素是患者代谢并从体内消除该药物的能力。因此，在开始治疗之前确定药物处理能力受损的个人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中起着关键作用。有效的肝脏消除需要几个过程，包括摄取转运体进入肝细胞，第一阶段和第二阶段的生物转化，以及药物转运体从肝脏排出到胆汁或回到血液中。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将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的风险更高的患者以及可能导致NASH患者不良事件的药物方面具有广泛的意义。我们在啮齿动物模型和患有NASH的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著变化，药物处置的功能发生了转变。需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体的表达和功能，从而增加了NASH儿童药物不良反应的风险；(2)APAP-GLUC水平可以作为代谢组生物标志物来识别这些(NASH)患者可能有药物不良反应的风险。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。目的2.确定脂肪肝患者APAP代谢产物的功能配置是否发生改变。目的3.检测脂肪变性和非酒精性脂肪肝患者肝脏中II、III期药物代谢酶和转运蛋白的表达和活性是否发生改变。

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.