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

描述：（改编自研究者摘要）据称，大多数 老年人的临床药理学研究包括少量的 70 - 75岁的健康人，白色人。这 申请旨在扩展与年龄相关的药代动力学和药物 包括老年人、体弱者、男性和女性，以及 少数群体此外，建议检查饮食对药物的影响 代谢和清除。 该提案的目标如下： 1)确定种族、性别、虚弱、药物联合给药的影响 和饮食对药物清除的影响。 这将解决许多假设，包括： 首过CYP 3A底物药物，如维拉帕米和硝苯地平， 具有低清除率和低第一性的多通道底物 与高加索人相比，非裔美国人的代谢水平降低;以及 B）与性别、临床虚弱（定义）、其他影响相关的假设 将对门诊病人进行药物和饮食摄入测试， 延伸护理机构。 每种药物约有350名患者，其中至少有100名受试者身体虚弱， 在家或机构，将包括在内。大量数据将 以系统的方式从受试者中收集，包括详细的饮食 历史将在给药后2 - 12 h进行血液采样，以估计 硝苯地平、维拉帕米、去甲维拉帕米和拜新同的血浆浓度 HPLC和GC/ECD。将使用平衡透析进行蛋白结合。 将使用NONMEM分析进行群体动力学，包括年龄、性别、 以逐步方式添加虚弱和其他协变量。 2)确定药物治疗中种族和性别差异的机制 间隙 传统方法将用于解决以下假设：a）种族 影响口服硝苯地平和维拉帕米的清除率，但不影响静脉内的清除率， 非裔美国人和高加索人男性和女性的自我选择饮食; B） 因此，标准饮食将消除差异; c）肠道代谢是 种族差异的原因（通过CYP 3A肠道抑制消除） 生物利用度而非性别（未被CYP 3A肠道抑制作用消除） 差异; d）性别差异反映了较高的肝脏和肠道 女性的清除率;和e）种族差异与饮食有关， 被标准饮食所取代。 药代动力学研究将在年轻和老年健康男性中进行， 女性、白色和非洲裔美国志愿者。个人将被给予iv 在受控条件下口服硝苯地平和维拉帕米并采集血样 将进行药物/代谢物测定和药代动力学分析。 尽可能在相同受试者中进行口服药代动力学研究 硝苯地平和维拉帕米进行后葡萄柚汁，以阻止 肠道CYP 3A。 计划进行进一步研究，以比较维拉帕米和/或维拉帕米的口服药代动力学。 硝苯地平在类似的受试者标准化饮食。

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.