OLDER PERSONS AND DRUGS--RACE, GENDER, AND AGE EFFECTS

描述：(改编自调查人员摘要)据报道，大多数 老年人的临床药理学研究包括少量的 年龄在70岁至75岁以下且为白人的健康个体。这 应用旨在扩大年龄相关药代动力学和药物的研究 代谢包括老年人、体弱者、男性和女性，以及 少数族裔。此外，还建议研究饮食对药物的影响。 新陈代谢和清除。 这项建议的目的如下： 1)确定种族、性别、脆弱、药物联合给药的影响 用种群动力学技术研究饮食对患者药物清除的影响。 这将解决许多假设，包括：a)清除高 先通过细胞色素P3A底物药物，如维拉帕米和硝苯地平，但不能 氨氯地平(低清除率、低First的多CYP途径底物 与高加索人相比，非裔美国人的PASS代谢)减少；以及 B)与性别、临床脆弱性、其他因素的影响有关的假设 药物和饮食摄入量将在门诊和医院的患者身上进行测试 长期护理机构。 每种药物约有350名患者，其中至少有100名受试者身体虚弱， 居家或制度化，将被包括在内。大量的数据将被 以系统的方式从受试者那里收集，包括详细的饮食 历史。服药后2-12小时采血以评估 硝苯地平、维拉帕米、去甲维拉帕米和氨氯地平的血药浓度 高效液相色谱法和GC/ECD联用。蛋白质结合将使用平衡透析进行。 人口动力学将使用NONMEM分析进行，包括年龄、性别、 脆弱性和其他协变量以逐步的方式相加。 2)确定药物中种族和性别差异的机制 通行证。 将使用传统方法来解决以下假设：a)种族 影响硝苯地平和维拉帕米的口服清除，但不影响静脉注射 非裔美国人和高加索男性和女性的自选饮食；b) 因此，标准饮食将消除差异；c)肠道新陈代谢是 种族差异的原因(被CYP3A肠道抑制废除) 生物利用度，而不是性别(不会被CYP3A肠道抑制所废除) 差异；d)性别差异反映了较高的肝脏和肠道 女性的性别差异；以及e)种族差异与饮食和 被标准饮食废除了。 药代动力学研究将在年轻和老年、健康的男性和 女性、白人和非裔美国人志愿者。个人将被给予静脉注射和 控制条件下口服硝苯地平和维拉帕米及采血 将用于药物/代谢物分析和药代动力学分析。 尽可能多的相同受试者进行口服药代动力学研究 西柚汁阻断后给予硝苯地平和维拉帕米 肠道细胞色素P3A。 计划进行进一步的研究，比较维拉帕米和/或维拉帕米的口服药代动力学。 硝苯地平在相似的受试者中进行标准化饮食。

DESCRIPTION: (adapted from Investigator's abstract) It is stated that most clinical pharmacology studies in older persons have included small numbers of individuals who were healthy, under 70 to 75 years and were white. This application seeks to extend the study of age related pharmacokinetics and drug metabolism to include older persons, frail individuals, males and females, and minorities. Furthermore, it is proposed to examine the effect of diet on drug metabolism and clearance. The proposal has the following aims: 1) To determine the effects of race, gender, frailty, drug co-administration and diet on drug clearance in patients using population kinetic techniques. This will address numerous hypotheses including: a) That clearance of high first pass CYP3A substrate drugs such as verapamil and nifedipine but not amlodipine (multiple CYP pathway substrate with low clearance and low first pass metabolism) is decreased in African Americans compared to Caucasians; and b) Hypotheses related to effects of gender, clinical frailty (defined), other drugs and dietary intake will be tested in patients from outpatient clinics and extended care institutions. About 350 patients on each drug, with at least 100 subjects being frail, homebound or institutionalized, will be included. Extensive data will be collected in a systematic fashion from the subjects, including detailed dietary history. Blood sampling will be performed 2 - 12 h after dose for estimation of plasma concentrations of nifedipine, verapamil, norverapamil, and amlodipine by HPLC and GC/ECD. Protein binding will be performed using equilibrium dialysis. Population kinetics will be performed using NONMEM analysis with age, gender, frailty and other covariates added in stepwise fashion. 2) To determine the mechanism for race and gender differences in drug clearance. Traditional methods will be used to address the following hypotheses: a) Race affects oral but not iv clearance of nifedipine and verapamil due to effects of self selected diet in African American and Caucasian men and women; b) That standard diet thus will eliminate differences; c) That gut metabolism is the reason for racial differences (abolished by CYP3A gut inhibition) in bioavailability but not gender (not abolished by CYP3A gut inhibition) differences; d) Gender differences reflect higher hepatic and intestinal clearance in females; and e) Ethnic differences are related to diet and abolished by standard diet. Pharmacokinetic studies will be performed in young and older, healthy male and female, white and African American volunteers. Individuals will be given iv an oral nifedipine and verapamil under controlled conditions and blood sampling will be performed for drug/metabolite assays and pharmacokinetic analysis. As much as possible the same subjects will have oral pharmacokinetic studies of nifedipine and verapamil performed following grapefruit juice to block intestinal CYP3A. Further studies are planned to compare oral pharmacokinetics of verapamil and/ nifedipine in similar subjects on a standardized diet.