CYP3A Function in Aging AfricanAmericans

描述（由申请人提供）：细胞色素P450-3A（CYP 3A） 药物代谢酶负责生物转化， 清除了当代临床使用的大量药物 治疗学CYP 3A表达和活性的个体差异， 在肝脏和胃肠道（GI）粘膜中，似乎是 药代动力学和对以下药物的反应的大部分个体差异 作为CYP 3A底物的治疗性给药。许多 临床研究表明，年龄、性别和种族（人种）可能是 以可预测的方式来计算这种变化的组成部分。例如，一些数据 提示某些CYP 3A药物清除：a老年时减少; B 女性高于男性; c非裔美国人高于 白种人然而，现有数据并不一致。 此外，CYP 3A 4、CYP 3A 5和孕烷-X受体基因的变异体可能 调节CYP 3A功能中与年龄、性别或种族相关的变异， 不被理解的方式。本研究将前瞻性评估以下队列： 年轻（18-45岁）、“年轻”老年人（60-69岁）和“老年”老年人（>70 志愿者，由非洲裔美国人和白人男性和女性组成。 研究范式将评估：a.肝血流量（HBF），基于清除率 B低剂量静脉利多卡因的药代动力学和药效学 静脉和口服咪达唑仑，一种“纯”CYP 3A底物; CYP 3A 4、CYP 3A 5和孕烷-X受体基因的变异，使用分子生物学方法， 基因技术; d.生物活性物质的血浆浓度 睾酮.从.和B.，可以通过以下方法估计咪达唑仑清除率： 两种途径、净口服生物利用度和归因于 肝和胃肠道系统前提取。与适当 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 CYP 3A基因变异和生物活性睾酮。本研究 应该提供关于年龄，性别， 和种族作为CYP 3A介导的药物代谢变异性的来源， 反应

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.