Drug Metabolism and Chronic Liver Disease

描述（由申请人提供）：这是一份重新提交的申请，其目标是利用药理学原理更好地了解丙型肝炎相关肝脏疾病对药物处置的影响，并开发新的工具来评估肝功能。我们建议解决以下特定假设：在特定目标1中：与匹配对照相比，丙型肝炎影响代谢药物的清除率。此外，被不同药物代谢酶代谢的药物的清除率变化程度不同，这与肝脏疾病的严重程度有关。特异性目的2：无肝失代偿的丙型肝炎患者的药物代谢选择性降低与酶特异性下调肝脏中该酶mRNA的表达以及细胞因子、白细胞介素-6和肿瘤坏死因子- ?的循环水平升高有关。具体目标3：多种药物代谢酶活性的测量可以在连续的、进行性肝功能模型的背景下进行解释，以提供对丙型肝炎患者肝功能和预后的综合评估。我们建议研究慢性持续性肝炎、慢性活动性肝炎和肝硬化伴或不伴肝功能失代偿的丙型肝炎患者（n= 112）和年龄、性别匹配的对照组（n=48）两种情况。每个研究对象将参加三个药代动力学（PK）研究，这些研究使用选定的药物作为主要或完全由单个药物代谢酶代谢的底物的探针。第一部分：鸡尾酒包括：咖啡因（CYP1A2）、氟比洛芬（CYP2C9）、甲苯妥英（CYP2C19）、碎片喹（CYP2D6）、氯唑酮（CYP2E1）和氨苯砜（乙酰化）。第2部分：半同时口服：静脉给予咪达唑仑以测量肠道和肝脏对CYP3A代谢的贡献。第3部分：同时口服对乙酰氨基酚（UGT1A6）和静脉注射吗啡（UGT2B7）。在可行的情况下，作为常规患者护理的一部分，在诊断性肝活检时获得的肝组织将测量CYP1A2、CYP2C9、CYP2C19、CYP2D6、CYP2E1、CYP3A4、CYP3A5、UGT1A6和UGT2B7 mRNA的浓度。丙型肝炎相关肝病患者将每隔6个月随访一次，直到肝移植、死亡或资金持续时间。该研究将在临床状态改变后或肝病患者在2年后以及对照受试者在1或12个月后重复进行。总的来说，这些研究将在同一组丙型肝炎患者和正常受试者中提供巩固的信息基础，以更好地了解丙型肝炎相关活性疾病对药物代谢酶的影响。这些信息有可能创造新的综合指标来评估肝功能和预后。

DESCRIPTION (provided by applicant): This is a resubmission of a proposal whose goal is to use pharmacogenetic principles to better understand the influence of liver disease associated with hepatitis C on drug disposition and develop new tools to evaluate hepatic function. We propose to address the following specific hypotheses: In Specific Aim 1: Hepatitis C influences the clearance of drugs that undergo metabolism in comparison to matched controls. Furthermore, the extent of change in clearance is different for drugs that are metabolized by different drug metabolizing enzymes and is associated with the severity of the liver disease. Specific Aim 2: Selective decreases in drug metabolism in patients with hepatitis C without hepatic decompensation is associated with enzyme specific down-regulation of hepatic expression of mRNA for that enzyme and increased circulating levels of the cytokines, Interleukin-6 and Tumor Necrosis Factor- ?. Specific Aim 3: The measurement of activity of multiple drug metabolizing enzymes can be interpreted in the context of a sequential, progressive model of hepatic dysfunction to provide an integrated assessment of hepatic function and prognosis in patients with hepatitis C. We propose to study patients with hepatitis C (n= 112) associated with chronic persistent hepatitis, chronic active hepatitis and cirrhosis with or without hepatic decompensation and age, sex matched controls (n=48) on two occasions. Each study subject will participate in three pharmacokinetic (PK) studies that uses drugs selected as probes of substrates metabolized predominantly or exclusively by an individual drug metabolizing enzyme. Part 1: A cocktail to include: caffeine (CYP1A2), flurbiprofen (CYP2C9), mephenytoin (CYP2C19), debrisoquine (CYP2D6), chlorzoxazone (CYP2E1) and dapsone (acetylation). Part 2: Semi-simultaneous oral:intravenous administration with midazolam to measure intestinal and hepatic contributions to CYP3A metabolism and Part 3: oral administration of acetaminophen (UGT1A6) simultaneously with intravenous morphine (UGT2B7). When feasible, liver tissue obtained at the time of diagnostic liver biopsy as part of routine patient care will have concentrations of mRNA for CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, UGT1A6 and UGT2B7 measured. Patients with hepatitis C-associated liver disease will be followed at 6 monthly intervals until liver transplantation, death or duration of funding. The study will be repeated either after a change in clinical status or at 2 years in patients with liver disease and after one or 12 months in control subjects. Collectively, these studies will provide a consolidated base of information within the same cohort of patients with hepatitis C and normal subjects to better understand the influence of hepatitis C-associated live disease on drug metabolizing enzymes. This information has potential to create new integrated indices to evaluate hepatic function and prognosis.