Mechanisms of Atypical Drug Kinetics and Interactions

非典型药物动力学和相互作用的机制

• 批准号: 6520509
• 负责人: TIMOTHY S. TRACY
• 金额: $ 22.1万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6520509
• 关键词: binding sites; chemical kinetics; clinical research; computer simulation; cytochrome P450; drug adverse effect; drug interactions; drug metabolism; enzyme substrate; enzyme substrate analog; human subject; intermolecular interaction; isozymes; methylation; model design /development; molecular dynamics; nonsteroidal antiinflammatory agent; nuclear magnetic resonance spectroscopy; pharmacokinetics; physical model; protein structure function; racemization; rifamycins; site directed mutagenesis; structural biology

DESCRIPTION: (Adapted from the Applicant's Abstract): Toxicological consequences may occur when drug interactions involve drugs with narrow therapeutic indices such as the cytocbrome P450 2C9 (CYP2C9) substrates warfarin and phenytoin. To minimize risk to humans, accurate predictions of in vivo drug metabolism, pharmacokinetics and drug interactions from in vitro data are needed. Recently, careful examination of drug metabolism kinetic data has demonstrated that atypical kinetics of cytochrome P450 mediated reactions may occur with greater frequency than previously believed. Atypical kinetic profiles such as autoactivation, activation and substrate inhibition have been observed for several P450 isoforms including CYP2C9. These atypical kinetic processes may be either homotropic (involving only one substrate) or heterotropic (involving a substrate and another effector/substrate). Since these kinetic patterns are observed in vitro and investigators use these in vitro data to predict in vivo pharmacokinetics, it is imperative that the mechanisms for these interactions be studied to form a better foundation for in vitro-in vivo predictions of human drug metabolism and drug interactions. We hypothesize that critical amino acid changes in the CYP2C9 enzyme can alter the degree of cooperativity observed, that key molecule structural characteristics are required for heterotropic cooperativity, that these cooperativity interactions can be modeled and cooperativity can be observed in vivo. Using expressed CYP2C9 allelic variants and site-directed mutagenesis, metabolism of CYP2C9 substrates, which exhibit various kinetic profiles, and their interactions with a known effector (and a series of structural analogs) will be studied and modeled. Additionally, in vivo studies of a CYP2C9 substrate and a known (in vitro) effector will be conducted. Taken together, these results will improve CYP2C9 in vitro-in vivo predictive capabilities.

描述：（改编自申请人的摘要）：毒理学 当药物相互作用涉及狭窄的药物时，可能会发生后果 治疗指标，例如细胞杂交P450 2C9（CYP2C9）底物 华法林和苯妥优。为了最大程度地降低对人类的风险，准确预测 体内药物代谢，药代动力学和药物相互作用来自体外数据 需要。最近，仔细检查药物代谢动力学数据已有 证明了细胞色素P450介导的反应的非典型动力学可能 发生的频率比以前认为的要高。非典型动力学 自动活化，激活和底物抑制等概况已是 观察到包括CYP2C9在内的几种P450同工型。这些非典型动力学 过程可以是同型（仅涉及一个底物）或 异位（涉及底物和另一个效应子/底物）。自从 在体外观察到这些动力学模式，研究人员在 体外数据以预测体内药代动力学，必须 研究这些相互作用的机制，以形成更好的基础 人类药物代谢和药物相互作用的体外预测。我们 假设CYP2C9酶中的关键氨基酸变化可以改变 观察到关键分子结构特征的合作程度 这些合作性是杂型合作所必需的 可以对相互作用进行建模，并且可以在体内观察到协同性。使用 表达的CYP2C9等位基因变体和位置定向诱变，代谢 CYP2C9底物，表现出各种动力学曲线及其 与已知效应子（以及一系列结构类似物）的相互作用将是 研究和建模。此外，对CYP2C9底物和A的体内研究 将进行已知的（体外）效应子。两者一起，这些结果将 改善CYP2C9体内预测能力。