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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 W.
Afiliación
  • Sheng J; 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.
  • Tran PN; 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.
  • Li Z; 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.
  • Dutta S; 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.
  • Chang K; 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.
  • Colatsky T; Seabrook Island, SC 29455, United States.
  • Wu WW; 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. Electronic address: Wendy.Wu@fda.hhs.gov.
J Pharmacol Toxicol Methods ; 88(Pt 2): 109-122, 2017.
Article en En | MEDLINE | ID: mdl-28830713
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 <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. 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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Arritmias Cardíacas / Miocitos Cardíacos / Canales de Potasio Éter-A-Go-Go / Loperamida Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: J Pharmacol Toxicol Methods Asunto de la revista: FARMACOLOGIA / TOXICOLOGIA Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Arritmias Cardíacas / Miocitos Cardíacos / Canales de Potasio Éter-A-Go-Go / Loperamida Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: J Pharmacol Toxicol Methods Asunto de la revista: FARMACOLOGIA / TOXICOLOGIA Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos