CYP3A Function in Aging AfricanAmericans

CYP3A 在衰老非洲裔美国人中的功能

• 批准号: 6475200
• 负责人: DAVID J GREENBLATT
• 金额: $ 23.78万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6475200
• 关键词: African American; adult human (21+); age difference; aging; biotransformation; blood flow measurement; caucasian American; clearance rate; clinical research; cytochrome P450; drug metabolism; epidemiology; gastrointestinal drug absorption; gender difference; gene expression; genetic polymorphism; human subject; lidocaine; liver metabolism; midazolam; molecular genetics; pharmacokinetics; racial /ethnic difference; testosterone

DESCRIPTION (provided by applicant): The Cytochrome P450-3A (CYP3A) drug-metabolizing enzymes are responsible for the biotransformation and clearance of a large number of drugs used in contemporary clinical therapeutics. Individual variation in the expression and activity of CYP3A, both in the liver and gastrointestinal (GI) tract mucosa, appears to underlie much of the large individual variability in pharmacokinetics and response to therapeutically-administered medications that are CYP3A substrates. Many clinical studies demonstrate that age, gender, and ethnicity (race) may account for components of this variation in predictable ways. For example, some data suggest that clearance of certain CYP3A drugs: a Becomes reduced in old age; b Is higher in women than in men; c Is greater in African-Americans than in Caucasians. However the available data are not by any means consistent. Furthermore, variants in the CYP3A4, CYP3A5, and Pregnane-X receptor genes may modulate age-, gender-, or ethnicity-related variations in CYP3A function in ways that are not understood. This study will prospectively evaluate cohorts of young (18-45 years), "young" elderly (60-69 years) and "old" elderly (>70 years) volunteers, consisting of African-American and Caucasian men and women. The study paradigm will assess: a. Hepatic blood flow (HBF), based on clearance of low-dose intravenous lidocaine; b Pharmacokinetics and pharrnacodynamics of intravenous and oral midazolam, a "pure" CYP3A substrate; c The prevalence of variants in the CYP3A4, CYP3A5, and pregnane-X receptor genes, using molecular genetic techniques; d. Plasma concentrations of biologically active testosterone. From a. and b., it is possible to estimate midazolam clearance by both routes, net oral bioavailability, and bioavailability attributable to hepatic and gastrointestinal presystemic extraction. With appropriate statistical techniques, the contributions of age, gender, and ethnicity to overall variance can be determined, as well as modulation of the relationships by genetic CYP3A variants and by biologically active testosterone. This study should provide important mechanistic information on the role of age, gender, and ethnicity as sources of variability in CYP3A-mediated drug metabolism and response.

描述（由申请人提供）：细胞色素 P450-3A (CYP3A) 药物代谢酶负责生物转化和 当代临床使用的大量药物的清除 疗法。 CYP3A 表达和活性的个体差异， 在肝脏和胃肠道粘膜中，似乎是 药代动力学和对药物的反应存在很大的个体差异 作为 CYP3A 底物的治疗药物。许多 临床研究表明，年龄、性别和种族（种族）可能是影响因素 以可预测的方式获取这种变化的组成部分。例如，一些数据 表明某些 CYP3A 药物的清除率： a 在老年时减少；乙 女性高于男性； c 在非裔美国人中比在 白种人。然而，现有数据无论如何都不一致。 此外，CYP3A4、CYP3A5 和 Pregnane-X 受体基因的变异可能 调节 CYP3A 功能的年龄、性别或种族相关变异 不被理解的方式。这项研究将前瞻性地评估队列 年轻（18-45岁）、“年轻”老年人（60-69岁）和“老年”老年人（>70岁） 年）志愿者，由非裔美国人和白人男性和女性组成。 研究范式将评估：基于清除率的肝血流量 (HBF) 小剂量静脉注射利多卡因； b 药代动力学和药效学 静脉注射和口服咪达唑仑，一种“纯”CYP3A 底物； c 患病率 CYP3A4、CYP3A5 和 pregnane-X 受体基因的变体，使用分子 遗传技术； d.生物活性物质的血浆浓度 睾酮。从a. b.，可以通过以下方式估计咪达唑仑清除率： 两种途径的净口服生物利用度和生物利用度归因于 肝脏和胃肠道系统前提取。与适当的 统计技术、年龄、性别和种族的贡献 可以确定总体方差以及关系的调节 通过遗传 CYP3A 变异和生物活性睾酮。这项研究 应提供关于年龄、性别、 和种族作为 CYP3A 介导的药物代谢变异性的来源 回复。