Blockage of hERG current and the disruption of trafficking as induced by roxithromycin

Han, Shengna; Yang, Shenghao; Duan, Yanyan; Sun, Xiaoyan; Qiu, Chen; Fan, Tingting; Ye, Zhen-Kun; Huang, Chen‐Zheng; Hu, Xiangjie; Zhao, Zhigang; Zhang, Lirong

doi:10.1139/cjpp-2012-0456

Cited by 10 publications

(5 citation statements)

References 27 publications

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“…Macrolides are known to bind and inhibit the hERG channels (alpha-subunits). In addition, roxithromycin inhibits hERG channels and disrupts hERG protein trafficking [ 93 ] (Table 3 ). No information was found on whether other macrolide antibiotics disrupt hERG channel trafficking.…”

Section: Non-antiarrhythmic Drugs Associated With Increased Risk Of Tmentioning

confidence: 99%

Drug-induced Inhibition and Trafficking Disruption of ion Channels: Pathogenesis of QT Abnormalities and Drug-induced Fatal Arrhythmias

Cubeddu

2016

CCR

111

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Risk of severe and fatal ventricular arrhythmias, presenting as Torsade de Pointes (TdP), is increased in congenital and acquired forms of long QT syndromes (LQTS). Drug-induced inhibition of K+ currents, IKs, IKr, IK1, and/or Ito, delay repolarization, prolong QT, and increase the risk of TdP. Drug-induced interference with IKr is the most common cause of acquired LQTS/TdP. Multiple drugs bind to KNCH2-hERG-K+ channels affecting IKr, including antiarrythmics, antibiotics, antivirals, azole-antifungals, antimalarials, anticancer, antiemetics, prokinetics, antipsychotics, and antidepressants. Azithromycin has been recently added to this list. In addition to direct channel inhibition, some drugs interfere with the traffic of channels from the endoplasmic reticulum to the cell membrane, decreasing mature channel membrane density; e.g., pentamidine, geldalamicin, arsenic trioxide, digoxin, and probucol. Other drugs, such as ketoconazole, fluoxetine, norfluoxetine, citalopram, escitalopram, donepezil, tamoxifen, endoxifen, atazanavir, and roxitromycin, induce both direct channel inhibition and impaired channel trafficking. Although many drugs prolong the QT interval, TdP is a rare event. The following conditions increase the risk of drug-induced TdP: a) Disease states/electrolyte levels (heart failure, structural cardiac disease, bradycardia, hypokalemia); b) Pharmacogenomic variables (presence of congenital LQTS, subclinical ion-channel mutations, history of or having a relative with history of drug-induced long QT/TdP); c) Pharmacodynamic and kinetic factors (high doses, women, elderly, metabolism inhibitors, combining two or more QT prolonging drugs, drugs that prolong the QT and increase QT dispersion, and drugs with multiple actions on ion channels). Because most of these conditions are preventable, careful evaluation of risk factors and increased knowledge of drug use associated with repolarization abnormalities are strongly recommended.

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Section: Non-antiarrhythmic Drugs Associated With Increased Risk Of Tmentioning

confidence: 99%

Drug-induced Inhibition and Trafficking Disruption of ion Channels: Pathogenesis of QT Abnormalities and Drug-induced Fatal Arrhythmias

Cubeddu

2016

CCR

111

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“…In total, 1828 studies were retrieved from the literature search, of which, 97 (5%) were deemed eligible hERG/I Kr assays (Figure ). The characteristics of the eligible studies are detailed in Online Supplementary Table S3 . Eighty‐three (86%) of these studies provided IC50 values for at least 1 drug of interest.…”

Section: Resultsmentioning

confidence: 99%

Evidence for the hERG Liability of Antihistamines, Antipsychotics, and Anti‐Infective Agents: A Systematic Literature Review From the ARITMO Project

Hazell

Raschi

Ponti

et al. 2016

The Journal of Clinical Pharma

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A systematic review was performed to categorize the hERG (human ether-a-go-go-related gene) liability of antihistamines, antipsychotics, and anti-infectives and to compare it with current clinical risk of torsade de pointes (TdP). Eligible studies were hERG assays reporting half-minimal inhibitory concentrations (IC50). A "hERG safety margin" was calculated from the IC50 divided by the peak human plasma concentration (free C ). A margin below 30 defined hERG liability. Each drug was assigned an "uncertainty score" based on volume, consistency, precision, and internal and external validity of evidence. The hERG liability was compared to existing knowledge on TdP risk (www.credibledrugs.org). Of 1828 studies, 82 were eligible, allowing calculation of safety margins for 61 drugs. Thirty-one drugs (51%) had evidence of hERG liability including 6 with no previous mention of TdP risk (eg, desloratadine, lopinavir). Conversely, 16 drugs (26%) had no evidence of hERG liability including 6 with known, or at least conditional or possible, TdP risk (eg, chlorpromazine, sulpiride). The main sources of uncertainty were the validity of the experimental conditions used (antihistamines and antipsychotics) and nonuse of reference compounds (anti-infectives). In summary, hERG liability was categorized for 3 widely used drug classes, incorporating a qualitative assessment of the strength of available evidence. Some concordance with TdP risk was observed, although several drugs had hERG liability without evidence of clinical risk and vice versa. This may be due to gaps in clinical evidence, limitations of hERG/C data, or other patient/drug-specific factors that contribute to real-life TdP risk.

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“…Han et al found that mutations in drug-binding sites of the hERG channel could attenuate hERG current obstruction by roxithromycin, but did not significantly modify the disruption of trafficking [39]. According to Hancox et al study, D85N KCNE1 mutations demonstrated an increase in the sensitivity of IKr/hERG to inhibition with clarithromycin in vitro models [40].…”

Section: Original Articlementioning

confidence: 99%

Comparative Study of the Effect of Macrolide Antibiotics Erythromycin, Clarithromycin, and Azithromycin on the ERG1 Gene Expression in H9c2 Cardiomyoblast Cells

et al. 2020

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Macrolides are clinically well-established class of antibiotics. Macrolides induce cardiotoxicity by blocking ether-a-go-go–related gene (ERG) potassium channels in cardiac myocytes. The aim of this study was to compare the effects of erythromycin, clarithromycin and azithromycin on cell viability and expression of ERG1 gene in H9c2 cells. Cell viability and ERG1 gene expression of H9c2 cells in 3 different concentrations, 1, 10 and 25 µg/ml, after 48 and 72 h were determined by MTT test and Real time-PCR method respectively. After 48 h, the growth of H9c2 cells treated with erythromycin, clarithromycin and Azithromycin (except two doses) were inhibited significantly compared to control group (p<0.05). All three groups of antibiotics showed toxic effects on cells after 72 h in all concentrations. Azithromycin-inhibiting effects were significantly higher than two other groups after 72 h of treatment. The expression of ERG1 gene increased in all three groups of antibiotics by increasing the concentration and duration of treatment. Azithromycin had the most pronounced effect on ERG1 expression in 48 and 72 h. This study indicated that these macrolides affect ERG1 expression due to their potential cardiac adverse effects. Further investigations are required to understand the exact mechanism of cardiotoxicity associated with macrolides.

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Blockage of hERG current and the disruption of trafficking as induced by roxithromycin

Cited by 10 publications

References 27 publications

Drug-induced Inhibition and Trafficking Disruption of ion Channels: Pathogenesis of QT Abnormalities and Drug-induced Fatal Arrhythmias

Drug-induced Inhibition and Trafficking Disruption of ion Channels: Pathogenesis of QT Abnormalities and Drug-induced Fatal Arrhythmias

Evidence for the hERG Liability of Antihistamines, Antipsychotics, and Anti‐Infective Agents: A Systematic Literature Review From the ARITMO Project

Comparative Study of the Effect of Macrolide Antibiotics Erythromycin, Clarithromycin, and Azithromycin on the ERG1 Gene Expression in H9c2 Cardiomyoblast Cells

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