Sheng Jiansong, Tran Phu N, Li Zhihua, Dutta Sara, Chang Kelly, Colatsky Thomas, Wu Wendy W
Division of Applied Regulatory Science, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, the US Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, United States.
Seabrook Island, SC 29455, United States.
J Pharmacol Toxicol Methods. 2017 Nov-Dec;88(Pt 2):109-122. doi: 10.1016/j.vascn.2017.08.006. Epub 2017 Aug 19.
Loperamide (Immodium®) is indicated for symptomatic control of diarrhea. It is a μ-opioid receptor agonist, and recently has been associated with misuse and abuse. At therapeutic doses loperamide has not been associated with cardiotoxicity. However, loperamide overdose is associated with proarrhythmia and death - two effects that are likely attributable to its block of cardiac ion channels that are critical for generating action potentials. In this study, we defined loperamide-hERG channel interaction characteristics, and used a ventricular myocyte action potential model to compare loperamide's proarrhythmia propensity to twelve drugs with defined levels of clinical risk.
Whole-cell voltage-clamp recordings were performed at 37°C on a HEK293 cell line stably expressing the hERG channel proteins, and loperamide was bath-applied to assess its effects on hERG current. Loperamide suppressed hERG current in a use- and voltage-dependent but frequency-independent manner, with a half-maximal inhibitory concentration <90nM. The onset of current suppression was concentration-dependent and appeared to follow a first-order reaction. Loperamide also altered the voltage-dependence of steady state hERG current properties. Electrophysiological data were integrated into a myocyte model that simulated dynamic drug-hERG channel interaction to estimate Torsade de Pointes risk through comparisons with reference drugs with defined clinical risk. In the context of overdose that would result in loperamide levels far exceeding those produced by therapeutic doses, loperamide is placed in the high risk category, alongside quinidine, bepridil, dofetilide, and sotalol.
The combined in vitro and in silico approach provides mechanistic insight regarding the potential for loperamide to generate cardiotoxicity in overdose situations. This strategy holds promise for improving cardiac safety assessment.
洛哌丁胺（易蒙停®）用于腹泻的症状控制。它是一种μ-阿片受体激动剂，最近与误用和滥用有关。在治疗剂量下，洛哌丁胺与心脏毒性无关。然而，洛哌丁胺过量与心律失常和死亡有关——这两种效应可能归因于其对产生动作电位至关重要的心脏离子通道的阻断。在本研究中，我们确定了洛哌丁胺与hERG通道的相互作用特征，并使用心室肌细胞动作电位模型将洛哌丁胺致心律失常的倾向与十二种具有明确临床风险水平的药物进行比较。
在37°C下，对稳定表达hERG通道蛋白的HEK293细胞系进行全细胞电压钳记录，通过浴槽给药洛哌丁胺来评估其对hERG电流的影响。洛哌丁胺以使用和电压依赖性但频率非依赖性的方式抑制hERG电流，半数最大抑制浓度<90nM。电流抑制的起始呈浓度依赖性，似乎遵循一级反应。洛哌丁胺还改变了hERG电流特性的电压依赖性。将电生理数据整合到一个肌细胞模型中，该模型模拟动态药物-hERG通道相互作用，通过与具有明确临床风险的参考药物比较来估计尖端扭转型室性心动过速的风险。在过量用药导致洛哌丁胺水平远远超过治疗剂量所产生的水平的情况下，洛哌丁胺与奎尼丁、苄普地尔、多非利特和索他洛尔一样被归为高风险类别。
体外和计算机模拟相结合的方法为洛哌丁胺在过量用药情况下产生心脏毒性的可能性提供了机制性见解。这种策略有望改善心脏安全性评估。
