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.

代谢体内体外相关性的最新成功 基于药物相互作用表明酶的行为很大程度上取决于 保守的。然而，目前预测抑制的方法 基于的互动基本上仍然是定性的。对于无数 抑制剂，体外测定的抑制常数不足以充分 预测体内相互作用的程度。这些抑制剂似乎 体内比体外更有效。该领域的一个基本问题 体外-体内相关性是缺乏通用方法 获得酶位点处抑制剂的浓度和 该位点实际存在的抑制常数。在现在 应用程序中，我们将测试“游离药物假设”，即概念 抑制剂的效果由实际位点未结合的抑制剂控制 的酶。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是有效的 系统只要使用广泛的方法测量未结合的浓度 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“游离药物假说”。这将使用新的 参数，“抑制常数比”(R/kI)。理论表明 该比率（定义为 K/i/(pre)，在纯化的重组体中测定） 系统除以体内确定的 K/i/iv）将等于 1 并且 它将独立于酶。因此，本提案将提供一个有用的 根据所得数据进行体内定量预测的框架 体外。