DEFINING THE ACCESS PATH FOR LOCAL ANESTHETIC DRUGS

定义局部麻醉药物的获取路径

• 批准号: 6294524
• 负责人: PETER J LEE
• 金额: $ 4.73万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6294524
• 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.

电压门控钠离子通道在许多严重心律失常中起着重要作用，也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，但它们往往会导致心律失常，并可能导致心脏性猝死。它们的临床疗效和诱发心律失常的潜力可以归因于它们与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，以及由激活门和失活门保护的通往其结合部位的通路的不同使用。这些因素也是开放通道阻滞剂如氟卡胺和奎尼丁与灭活通道阻滞剂如利多卡因和美西律临床行为差异的基础。目前的方案分三个部分解决药物通路的问题：1)确定利多卡因是否使用外部亲水通路来影响其药代动力学，2)开发方法来确定在药代动力学中重要的亲水和疏水通路，以及3)调查开放通道和灭活通道阻断药物所使用的通路的可能差异。这项研究还可能进一步了解在药物-通道相互作用中重要的Na+通道的结构特征，并为更安全的使用和抗心律失常药物的新设计提供更好的见解。