AGING EFFECT ON DRUG BIOAVAILABILITY

老化对药物生物利用度的影响

基本信息

批准号：
6029809
负责人：
STEPHEN D HALL
金额：
$ 16.77万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-07-20 至 2000-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (Adapted from the Applicant's Abstract): The elderly (individuals over the age of 65) are the most medicated segment of society and account for 12% of the US population, increasing to 17% over the next 25 years. In part due to the polypharmacy that the elderly experience, there is a high incidence of drug-drug interactions in this group which is also particularly vulnerable to drug toxicity. A large number of commonly used drugs are eliminated from the body by oxidative metabolism catalyzed by the 3A sub-family of the cytochrome P450 (CYP) super family of enzymes. It is clear that for CYP3A substrates the systemic clearance is reduced and bioavailability increased in the elderly, but it is unclear whether these changes result in an increased potential for drug-drug interactions in the elderly. The bioavailability of CYP3A substrates is determined in large part by the extent of first-pass extraction of these drugs in the intestinal wall and the liver. The intestinal and hepatic CYP3A enzymes are independently regulated. Therefore the changes in clearance and bioavailability of CYP3A substrates observed in the elderly may reflect selective changes in the extraction drugs at intestinal and hepatic sites, which may in turn impact upon the incidence of drug-drug interactions in the elderly. This proposal will examine whether or not advanced age exaggerates the pharmacokinetic and pharmacodynamic outcome of drug-drug interactions. The effect of a CYP3A inhibitor (clarithromycin) and inducer (rifampin) on the intestinal availability, intestinal intrinsic clearance, hepatic availability and hepatic intrinsic clearance of midazolam will be quantified in young and elderly, male and female human volunteers. By means of a newly developed phenotyping procedure the investigators will examine whether the magnitude of the drug-drug interactions in these groups of human volunteers can be predicted by the dextromethorphan CYP3A urinary metabolic ratio. To directly address the hypothesis that aging and/or gender modulates intestinal CYP3A they will determine the amount, by immunoblotting, and catalytic activity of CYP3A in human duodenal biopsy tissue. Aging and gender differences in CYP3A activity will also be examined in a recently developed, chronically cannulated rat model. The latter approach allows a rigorous evaluation of 1) The extraction of CYP3A substrates by intestinal and hepatic first-pass sites in young, middle-aged and elderly rats of male and female genders. 2) The determinants of the magnitude of drug-drug interactions with CYP3A inhibitors and inducers in these animal groups. The intent of these studies is to provide a clear understanding of the mechanism of the interactions between midazolam and macrolide antibiotics in the elderly. However, the choice of model compounds will also provide a general understanding of the mechanism of interactions between CYP3A substrates and the modulation of these interactions by advanced age.

描述（改编自申请人的摘要）：老年人（65岁以上的个人）是社会上最受欢迎的细分市场并占美国人口的12％，在接下来的25个中增加到17％年。部分原因是老年人经历的多剂量是该组中药物相互作用的高发病率特别容易受到药物毒性的影响。大量常用药物通过氧化代谢从体内消除 3A细胞色素P450（CYP）超级酶的亚家族。这是显然，对于CYP3A底物，系统清除率降低，并且老年人的生物利用度增加了，但尚不清楚这些是否存在变化导致在药物相互作用的潜力增加老年。 CYP3A底物的生物利用度在很大程度上由这些药物在肠壁上的第一频繁提取的程度肝脏。肠道和肝CYP3A酶是独立的受监管。因此，CYP3A的清除和生物利用度的变化在老年人中观察到的底物可能反映了在肠道和肝脏部位的提取药物，这可能又可能影响在老年人中毒品相互作用的发生率。该提议将检查高龄是否夸大了药物相互作用的药代动力学和药效性结果。这 CYP3A抑制剂（Clarithromycin）和诱导剂（利福丁）对肠道可用性，肠内固有间隙，肝将量化咪达唑仑的可用性和肝内在清除率在年轻人和老年人中，男性和女性志愿者。通过新的开发的表型程序研究人员将检查这些人类志愿者中药物相互作用的大小可以通过右美甲状腺CYP3A尿代谢比预测。直接解决衰老和/或性别调节的假设肠CYP3A他们将通过免疫印迹确定金额，并 CYP3A在人十二指肠活检组织中的催化活性。 CYP3A活性的衰老和性别差异也将在A中检查最近开发的，长期插管的大鼠模型。后一种方法允许对1）通过年轻，中年和老年人的肠道和肝第一通站点男性和女性的大鼠。 2）大小的决定因素这些动物中与CYP3A抑制剂和诱导剂的药物相互作用组。这些研究的目的是对在老人。但是，模型化合物的选择也将提供对CYP3A之间相互作用机制的一般理解底物和这些相互作用的调制。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Human cytochrome P450 3A (CYP3A) mediated midazolam metabolism: the effect of assay conditions and regioselective stimulation by alpha-naphthoflavone, terfenadine and testosterone.

DOI：
10.1097/00008571-199804000-00007
发表时间：
1998-04
期刊：
Pharmacogenetics
影响因子：
0
作者：
Jukka M??enp????-Jukka-Menp-2231377422;S. Hall;B. Ring;S. Strom;S. Wrighton
通讯作者：
Jukka M??enp????-Jukka-Menp-2231377422;S. Hall;B. Ring;S. Strom;S. Wrighton

Diltiazem inhibition of cytochrome P-450 3A activity is due to metabolite intermediate complex formation.

地尔硫卓对细胞色素 P-450 3A 活性的抑制是由于代谢物中间复合物的形成。