Older Persons & Drugs: race, gender, and age effects

描述(由申请人提供)： 我们的总体目标是确定药物清除的决定因素，以改善老年患者的药物治疗。存在估计年龄、性别和种族对肾脏药物清除量影响的算法。对于非肾脏药物清除，没有这样的算法存在。因为大多数非肾脏清除的药物都是由CYP3A代谢的，所以我们开始了对这种酶清除的药物的研究。我们已经完成了在患者群体中稳定状态CYP介导的药物清除的第一次研究，其中包括大量女性、高龄(&gt；80岁)以及辅助生活和长期护理设施的居民。我们使用了总体方法，允许从个人中进行稀疏抽样。令我们惊讶的是，65-90岁的患者和年龄最大的养老院居民的清除率是最高的。与年龄相关的发现与三种在药理学特性(生物利用度和转运体亲和力)方面差异很大的CYP3A底物药物一致。我们还发现，与男性相比，女性的清除速度更快，并确定了影响男性清除的协变量(吸烟、饮酒)，但在女性或年龄最大的患者中没有。白人、黑人和拉美裔美国人的通过率也因种族而异。饮食分析表明，维生素D的摄入量会影响细胞色素P3A的清除率。这些结果表明，不包括高龄、女性和少数群体的生理性衰老研究可能不能反映接受药物治疗的老年患者的清除特征。我们建议在不同的临床人群中进行CYP3A底物阿托伐他汀的人群研究，并进行干预性研究，以探索老年患者保持清除率的潜在机制，并首次进行CYP2C19介导的兰索拉唑清除率的人群研究，以调查年龄、性别和基因(种族)对这种重要多态酶稳态清除率的影响。这些发现对护理越来越多的高龄患者，特别是研究不足的妇女和少数群体的潜在影响是巨大的。

DESCRIPTION (provided by applicant): Our overall goals are to identify determinants of drug clearance to improve medication therapy for older patients. Algorithms to estimate age, sex, and race effects on renal drug clearance exist. No such algorithms exist for non-renal drug clearance. Because the majority of non-renally cleared medications are metabolized by CYP3A, we began studies with drugs cleared by this enzyme. We have completed the first studies of steady-state CYP-mediated drug clearance in patient populations that include significant numbers of women, the very old (>80 years of age), and residents of assisted living and long-term care facilities. We used the population approach that allows sparse sampling from individuals. To our surprise, clearance rates were among the highest in patients from ages 65-90, and in the oldest nursing home residents. The age-related findings were consistent for three CYP3A substrate drugs that varied widely in pharmacological properties (bioavailabiltiy and transporter affinity). We also found faster clearance in women compared to men and identified covariates (smoking, alcohol intake) that affected clearance in men, but were not present in women, or the oldest patients. Clearance rates also varied by race with whites> blacks and > Hispanics. Dietary analyses suggest vitamin D intake influences CYP3A clearance rates. These results suggest studies of physiologic aging excluding the very old, women, and minority groups may not reflect clearance characteristics in older patients Ithat receive medications. We propose population studies of a CYP3A substrate, atorvastatin, in diverse clinical populations with an interventional study to investigate a potential mechanism for preserved clearance rates in older patients, and the first population studies of CYP2C19- mediated clearance of lansoprazole to investigate age, sex, and genotype (race) effect on steady-state clearance rates of this important polymorphic enzyme. The potential impact of these findings on the care of the growing number of very old patients, especially understudied women and minority groups, is great.