PREDICTION OF DRUG INTERACTIONS IN VIVO AND IN VITRO

体内和体外药物相互作用的预测

• 批准号: 6643651
• 负责人: WILLIAM F TRAGER
• 金额: $ 25.41万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6643651
• 关键词: active sites; blood chemistry; cytochrome P450; drug interactions; drug metabolism; enzyme activity; enzyme inhibitors; fentanyl; human subject; mexiletine; microsomes; midazolam; omeprazole; pharmacokinetics; phenytoin; protein binding; protein isoforms; theophylline; tolbutamide; urinalysis; valproate

The recent successes of in vivo-in vitro correlations for metabolically based drug interactions suggests that enzyme behavior is largely conserved. However, current approaches to the prediction of inhibition based interactions have remained essentially qualitative. For numerous inhibitors, inhibition constants determined in vitro do not adequately predict the extent of interaction in vivo. These inhibitors appear to be more potent in vivo than in vitro. A fundamental problem in the field of in vitro-in vivo correlations is the absence of a general methodology for obtaining the concentration of inhibitor at the enzyme site and the inhibition constant that actually prevails at the site. In the present application, we will test the "free drug hypothesis," i.e. the concept that inhibitor effect is governed by unbound inhibitor at the actual site of the enzyme. In the first two specific aims, we will demonstrate that the free drug hypothesis is valid for competitive inhibitors in in vitro systems so long as unbound concentrations are measured using an extensive list of inhibitors with different protein binding and lipophilicity characteristics. Specific Aims 2(a) and 2(b) will test the validity of the "free drug hypothesis" in vivo. This will be accomplished using a new parameter, the "inhibition constants ratio" (R/kI). Theory suggests that this ratio (defined as K/i/(pre) determined in a purified recombinant system divided by the K/i/iv determined in vivo) will equal one and that it will be independent of enzyme. This proposal will thus provide a useful framework to effectuate quantitative in vivo predictions from data derived in vitro.

代谢中体内体外相关性的最新成功 基于药物的相互作用表明酶行为主要是 保守。但是，当前的抑制作用方法 基本的互动基本上是定性的。许多 抑制剂，在体外确定的抑制常数不能充分 预测体内相互作用的程度。这些抑制剂似乎是 比体内更有效的体内。领域的基本问题 体内体内相关性是没有一般方法论 在酶部位获得抑制剂的浓度和 在现场实际上占上风的抑制常数。现在 应用，我们将测试“免费药物假设”，即 这种抑制剂效应受实际部位未结合抑制剂的控制 酶。在前两个具体目标中，我们将证明 游离药物假说对于体外竞争性抑制剂有效 只要使用广泛的浓度来测量未结合的浓度 具有不同蛋白质结合和亲脂性的抑制剂列表 特征。具体目标2（a）和2（b）将测试 体内“游离药物假设”。这将使用新的 参数，“抑制常数比”（r/ki）。理论表明这一点 该比率（定义为在纯化的重组中确定的K/I/（PRE） 系统除以K/I/IV在体内确定的系统将等于一个，并且 它将独立于酶。因此，该建议将提供有用的 从得出的数据中实现定量预测定量的框架 体外。