DEFINING THE ACCESS PATH FOR LOCAL ANESTHETIC DRUGS

定义局部麻醉药物的获取路径

• 批准号: 6498554
• 负责人: PETER J LEE
• 金额: $ 2.31万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6498554
• 关键词: Xenopus; antiarrhythmic agent; chemical binding; disopyramide; lidocaine; local anesthetics; pharmacokinetics; sodium channel

The voltage-gated Na+ channel plays an important role in many serious arrhythmias and is the target of many antiarrhythmic drugs. While these drugs may control arrhythmia, they are often proarrhythmic and may contribute to sudden cardiac death. Their clinical efficacy and proarrhythmic potential can be attributed to their kinetic interaction with the Na+ channel. Major factors controlling their pharmacokinetics relate to the differential affinities toward gating states of the Na+ channel and differential uses of access paths to their binding site, guarded by activation and inactivation gates. These factors also underlie the differences in clinical behavior of open-channel blocking drugs such as flecainide and quinidine and inactivated-channel blocking drugs such as lidocaine and mexilitine. The current proposal addresses issues of drug- access paths in three parts; 1) to determine whether lidocaine uses an external hydrophilic path to affect its pharmacokinetics, 2) to develop methods to define hydrophilic and hydrophobic access paths important in the pharmacokinetics, and 3) to investigate possible differences in the access paths used by open-channel and inactivated-channel blocking drugs. The study may also result in further information on structural features of the Na+ channel important in drug-channel interaction and offer better insights for safer use and new design of antiarrhythmic drugs.

电压门控Na+通道在许多严重心律失常中发挥重要作用，是许多抗心律失常药物的靶点。虽然这些药物可以控制心律失常，但它们通常会导致心律失常，并可能导致心源性猝死。它们的临床疗效和致心律失常潜力可归因于它们与 Na+ 通道的动力学相互作用。控制其药代动力学的主要因素涉及对 Na+ 通道门控状态的不同亲和力以及通过激活和失活门保护的结合位点访问路径的不同使用。这些因素也是氟卡尼和奎尼丁等开放通道阻断药物与利多卡因和美西律等灭活通道阻断药物临床行为差异的基础。当前的提案分三个部分解决了药物获取途径的问题； 1) 确定利多卡因是否使用外部亲水路径来影响其药代动力学，2) 开发方法来定义药代动力学中重要的亲水和疏水进入路径，以及 3) 研究开放通道和失活通道阻断药物使用的进入路径可能存在的差异。该研究还可能获得有关药物通道相互作用中重要的Na+通道结构特征的更多信息，并为抗心律失常药物的更安全使用和新设计提供更好的见解。