Molecular Basis for the Lack of HERG K<sup>+</sup>Channel Block-Related Cardiotoxicity by the H<sub>1</sub>Receptor Blocker Cetirizine Compared with Other Second-Generation Antihistamines

Taglialatela, Maurizio; Pannaccione, Anna; Castaldo, Pasqualina; Giorgio, Giovanna; Zhou, Zhengfeng; January, Craig T.; Genovese, Arturo; Marone, Gianni; Annunziato, Lucio

doi:10.1124/mol.54.1.113

Cited by 122 publications

(86 citation statements)

References 34 publications

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“…Among them are terfenadine, astemizole, and cisapride. Published IC 50 values ranged between 56 and 431 nM for terfenadine (Rampe et al, 1997;Chachin et al, 1999) and between 69 and 480 nM for astemizole (Taglialatela et al, 1998;Chachin et al, 1999). Cisapride IC 50 values ranged between 4.3 nM in human embryonic kidney 293 cells (Anson et al, 2004) and 124 nM in Xenopus laevis oocytes (Fernandez et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

A Common Antitussive Drug, Clobutinol, Precipitates the Long QT Syndrome 2

Bellocq¹,

Wilders²,

Schott³

et al. 2004

Mol Pharmacol

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QT prolongation, a classic risk factor for arrhythmias, can result from a mutation in one of the genes governing cardiac repolarization and also can result from the intake of a medication acting as blocker of the cardiac K ϩ channel human ether-a-gogo-related gene (HERG). Here, we identified the arrhythmogenic potential of a nonopioid antitussive drug, clobutinol. The deleterious effects of clobutinol were suspected when a young boy, with a diagnosis of congenital long QT syndrome, experienced arrhythmias while being treated with this drug. Using the patch-clamp technique, we showed that clobutinol dose-dependently inhibited the HERG K ϩ current with a half-maximum block concentration of 2.9 M. In the proband, we identified a novel A561P HERG mutation. Two others long QT mutations (A561V and A561T) had been reported previously at the same position. None of the three mutants led to a sizeable current in heterologous expression system. When coexpressed with wildtype (WT) HERG channels, the three Ala561 mutants reduced the trafficking of WT and mutant heteromeric channels, resulting in decreased K ϩ current amplitude (dominant-negative effects). In addition, A561P but not A561V and A561T mutants induced a ϷϪ11 mV shift of the current activation curve and accelerated deactivation, thereby partially counteracting the dominant-negative effects. A561P mutation and clobutinol effects on the human ventricular action potential characteristics were simulated using the Priebe-Beuckelmann model. Our work shows that clobutinol has limited effects on WT action potential but should be classified as a "drug to be avoided by congenital long QT patients" rather than as a "drug with risk of torsades de pointes".

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Section: Discussionmentioning

confidence: 99%

A Common Antitussive Drug, Clobutinol, Precipitates the Long QT Syndrome 2

Bellocq¹,

Wilders²,

Schott³

et al. 2004

Mol Pharmacol

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“…More recently, newer H 1 -receptor antagonists, terfenadine and astemizole, were withdrawn from the market because of TdP occurrence (5 -9). These antagonists have been shown to inhibit cardiac I Kr currents in a concentrationdependent manner with IC 50 values of 0.35 -0.45 μM (3,21). The hydroxyzine IC 50 for HERG currents (0.62 μM) in our study is close to its reported maximum serum concentration in humans (0.16 μM after a single oral dose of 0.7 mg / kg hydroxyzine), and the drug has a very long washout time (t 0.5 = 20 h) (22,23).…”

Section: Discussionmentioning

confidence: 99%

Hydroxyzine, a First Generation H1-Receptor Antagonist, Inhibits Human Ether-a-go-go–Related Gene (HERG) Current and Causes Syncope in a Patient With the HERG Mutation

et al. 2008

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Abstract. QT prolongation, a risk factor for arrhythmias, can result from genetic variants in one (or more) of the genes governing cardiac repolarization as well as intake of drugs known to affect a cardiac K + channel encoded by human ether-a-go-go-related gene (HERG). In this paper, we will report a case of drug-induced long QT syndrome associated with an H 1 -receptor antagonist, hydroxyzine, in which a mutation was identified in the HERG gene. After taking 75 mg of hydroxyzine for several days, a 34-year-old female began to experience repetitive syncope. The deleterious effect of hydroxyzine was suspected because QTc interval shortened from 630 to 464 ms after cessation of the drug. Later on, the patient was found to harbor an A614V-HERG mutation. By using the patch-clamp technique in the heterologous expression system, we examined the functional outcome of the A614V mutation and confirmed a dominantnegative effect on HERG expression. Hydroxyzine concentration-dependently inhibited both wild-type (WT) and WT / A614V-HERG K + currents. Half-maximum block concentrations of WT and WT / A614V-HERG K + currents were 0.62 and 0.52 µM, respectively. Thus, accidental combination of genetic mutation and intake of hydroxyzine appeared to have led to a severe phenotype, probably, syncope due to torsade de pointes.

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“…Terfenadine and hydroxyzine are lipophilic bases with high affinity for the I Kr channel, and have been found to cause prolongation of the QT interval in volunteers and patients. Their major metabolites, fexofenadine and cetirizine, are much more selective at H1 antagonism versus I Kr blocking (Carmeliet, 1998;Taglialatela et al, 1998;Anthes et al, 2002;Chiu et al, 2004) due to their zwitterionic nature (both are carboxylic acid metabolites). The structure-activity relationships of the I Kr channel render zwitterionic compounds extremely unlikely to have affinity and activity (Paakkari, 2002).…”

Section: When Are Metabolites Toxic and What Considerationsmentioning

confidence: 99%

SEEING THROUGH THE MIST: ABUNDANCE VERSUS PERCENTAGE. COMMENTARY ON METABOLITES IN SAFETY TESTING

Smith¹,

Obach²

2005

Drug Metab Dispos

131

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ABSTRACT:Recent attention has been given to the potential roles that metabolites could play in safety evaluations of new drugs. In 2002, a proposal was published on "metabolites in safety testing" ("MIST , which suggested some guidelines regarding when it is necessary to provide greater assessment of the safety of metabolites. However, this proposal was based on relative abundance values, i.e., the percentage that a metabolite comprises of total exposure to drug-related material."In the present commentary, we propose that absolute abundance criteria be used rather than relative abundance. The absolute abundance of a metabolite in circulation or excreta in humans should be combined with other information regarding the chemical structure of the metabolite (e.g., similarity to the parent drug, presence of chemically reactive substituents) and potential mechanisms of toxicity (e.g., suprapharmacological effects, secondary pharmacological effects, nonspecific effects). Decision trees are described that can be used to address human metabolites in safety testing.Much attention has been given to the potential role that metabolites of drugs may contribute to drug-induced toxicity. Since possible mechanisms of toxicity are myriad and in many cases complex, gaining an understanding of the role that drug metabolites can contribute to this process is even more challenging than it is for the parent drug. It is not uncommon to speculate that a metabolite(s) could be responsible when toxicity is observed, either in toxicology studies conducted in laboratory animal species or as side effects in clinical trials. This speculation is particularly tempting when the toxicity observed has no apparent link to the target pharmacological mechanism. Such speculations often outnumber and dwarf the number of times that a metabolite is the actual cause. For instance, many publications have linked the teratogenesis associated with phenytoin to metabolites such as epoxides (Martz et al., 1977;Finnell et al., 1992;Raymond et al., 1995). When the pharmacology of the drug is fully considered, it is an I Kr channel blocker (hERG ED 50 ϳ100 M), in addition to its primary activity against the sodium channel (IC 50 ϳ47 M) (Nobile and Vercellino, 1997;Salvati et al., 1999). I Kr channel blockers, at concentrations not affecting the adult, cause bradycardia, arrhythmia, and cardiac arrest in the fetus, leading to hypoxia, reoxygenation and alterations in embryonic blood flow. These effects can lead to growth retardation, orofacial clefts, distal digital reduction, and cardiovascular defects (Salvati et al., 1999;Danielsson et al., 2001). Thus, phenytoin serves as an example in which it is tempting to propose that a metabolite is responsible for toxicity but that, in actuality, the toxicity is caused by the parent drug acting at a nontarget receptor.A drug can yield dozens of metabolites, and it is not a common practice to measure exposure to these metabolites in toxicology studies conducted early in the drug development process; besides, at this early ...

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Molecular Basis for the Lack of HERG K⁺Channel Block-Related Cardiotoxicity by the H₁Receptor Blocker Cetirizine Compared with Other Second-Generation Antihistamines

Cited by 122 publications

References 34 publications

A Common Antitussive Drug, Clobutinol, Precipitates the Long QT Syndrome 2

A Common Antitussive Drug, Clobutinol, Precipitates the Long QT Syndrome 2

Hydroxyzine, a First Generation H1-Receptor Antagonist, Inhibits Human Ether-a-go-go–Related Gene (HERG) Current and Causes Syncope in a Patient With the HERG Mutation

SEEING THROUGH THE MIST: ABUNDANCE VERSUS PERCENTAGE. COMMENTARY ON METABOLITES IN SAFETY TESTING

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Molecular Basis for the Lack of HERG K+Channel Block-Related Cardiotoxicity by the H1Receptor Blocker Cetirizine Compared with Other Second-Generation Antihistamines

Cited by 122 publications

References 34 publications

A Common Antitussive Drug, Clobutinol, Precipitates the Long QT Syndrome 2

A Common Antitussive Drug, Clobutinol, Precipitates the Long QT Syndrome 2

Hydroxyzine, a First Generation H1-Receptor Antagonist, Inhibits Human Ether-a-go-go–Related Gene (HERG) Current and Causes Syncope in a Patient With the HERG Mutation

SEEING THROUGH THE MIST: ABUNDANCE VERSUS PERCENTAGE. COMMENTARY ON METABOLITES IN SAFETY TESTING

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Molecular Basis for the Lack of HERG K⁺Channel Block-Related Cardiotoxicity by the H₁Receptor Blocker Cetirizine Compared with Other Second-Generation Antihistamines