Characterization of loperamide-mediated block of hERG channels at physiological temperature and its proarrhythmia propensity

Jiansong Sheng, Phu N. Tran, Zhihua Li, Sara Dutta, Kelly Chang, Thomas Colatsky, Wendy Wu

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Background 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. Methods and results 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 < 90 nM. 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. Conclusions 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.

Original languageEnglish (US)
Pages (from-to)109-122
Number of pages14
JournalJournal of Pharmacological and Toxicological Methods
Volume88
DOIs
StatePublished - Nov 1 2017
Externally publishedYes

Fingerprint

Loperamide
Temperature
Muscle Cells
Action Potentials
Electric potential
Bepridil
Pharmaceutical Preparations
Sotalol
Torsades de Pointes
Quinidine
HEK293 Cells
Clamping devices
Opioid Receptors
Baths
Ion Channels
Computer Simulation
Diarrhea

Keywords

  • Acquired long QT
  • Bepridil
  • CiPA
  • Cisapride
  • Clinical risk prediction
  • hERG
  • K11.1
  • Loperamide
  • QT interval
  • Torsade de pointes

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Cite this

Characterization of loperamide-mediated block of hERG channels at physiological temperature and its proarrhythmia propensity. / Sheng, Jiansong; Tran, Phu N.; Li, Zhihua; Dutta, Sara; Chang, Kelly; Colatsky, Thomas; Wu, Wendy.

In: Journal of Pharmacological and Toxicological Methods, Vol. 88, 01.11.2017, p. 109-122.

Research output: Contribution to journalArticle

Sheng, Jiansong ; Tran, Phu N. ; Li, Zhihua ; Dutta, Sara ; Chang, Kelly ; Colatsky, Thomas ; Wu, Wendy. / Characterization of loperamide-mediated block of hERG channels at physiological temperature and its proarrhythmia propensity. In: Journal of Pharmacological and Toxicological Methods. 2017 ; Vol. 88. pp. 109-122.
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abstract = "Background Loperamide (Immodium{\circledR}) 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. Methods and results 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 < 90 nM. 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. Conclusions 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.",
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T1 - Characterization of loperamide-mediated block of hERG channels at physiological temperature and its proarrhythmia propensity

AU - Sheng, Jiansong

AU - Tran, Phu N.

AU - Li, Zhihua

AU - Dutta, Sara

AU - Chang, Kelly

AU - Colatsky, Thomas

AU - Wu, Wendy

PY - 2017/11/1

Y1 - 2017/11/1

N2 - Background 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. Methods and results 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 < 90 nM. 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. Conclusions 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.

AB - Background 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. Methods and results 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 < 90 nM. 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. Conclusions 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.

KW - Acquired long QT

KW - Bepridil

KW - CiPA

KW - Cisapride

KW - Clinical risk prediction

KW - hERG

KW - K11.1

KW - Loperamide

KW - QT interval

KW - Torsade de pointes

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U2 - 10.1016/j.vascn.2017.08.006

DO - 10.1016/j.vascn.2017.08.006

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JO - Journal of Pharmacological and Toxicological Methods

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