CYP3A Function in Aging AfricanAmericans

CYP3A 在衰老非洲裔美国人中的功能

• 批准号: 6896140
• 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/6896140
• 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(申请人提供)：细胞色素P450-3A(CyP3A) 药物代谢酶负责生物转化和 现代临床中大量使用药物的清理 治疗学。CYP3A表达和活性的个体差异， 在肝脏和胃肠道(GI)粘膜中，似乎都是 药代动力学和对甲氧西林的反应中很大的个体变异性 治疗用药是以细胞色素P3A为底物的药物。许多 临床研究表明，年龄、性别和种族(种族)可能是 以可预测的方式获取此变体的组件。例如，一些数据 建议某些细胞色素P3A类药物的清除量：a在老年时减少；b 女性高于男性；非裔美国人的C高于#年。 高加索人。然而，现有的数据无论如何都不是一致的。 此外，CYP3A4、CYP3A5和孕烷-X受体基因的变异可能 调节CYP3A功能中与年龄、性别或种族相关的变异 不被理解的方式。这项研究将前瞻性地评估 年轻人(18-45岁)、“年轻”老年人(60-69岁)和“老年”老年人(&gt；70 年)志愿者，由非裔美国人和高加索人组成。 研究范式将评估：a.基于清除的肝血流量(HBF) 小剂量利多卡因静脉注射的药代动力学和药效学 静脉和口服咪达唑仑，一种“纯”的细胞色素P3A底物； CYP3A4、CYP3A5和孕烷-X受体基因的变异 基因技术；d.生物活性的血浆浓度 睾丸激素。根据a和b，可以通过以下方法估计咪达唑仑的清除量 两种途径，净口服生物利用度和生物利用度归因于 肝脏和胃肠系膜前抽提物。以适当的方式 统计技术，年龄、性别和种族对 可以确定总体方差以及关系的调制 通过基因突变的细胞色素P3A和生物活性的睾丸素。本研究 应提供有关年龄、性别、 在细胞色素P3A介导的药物代谢和药物代谢中作为变异源的种族 回应。