The inhibitory effect of the antipsychotic drug haloperidol on HERG potassium channels expressed in <i>Xenopus</i> oocytes

Suessbrich, Hartmut; Schönherr, Roland; Heinemann, Stefan H.; Attali, Bernard; Läng, Florian; Büsch, Andreas

doi:10.1038/sj.bjp.0700989

Cited by 215 publications

(152 citation statements)

References 31 publications

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“…It has been reported that haloperidol blocks other potassium channels, such as HERG, in a strongly voltage-dependent manner (Suessbrich et al, 1997). We examined this effect using cloned K ATP channels expressed in HEK293 cells (which do not possess significant endogenous voltage-dependent currents), to avoid interference from voltage-gated channels in b cells.…”

Section: Voltage Dependency Of Haloperidol Blockagementioning

confidence: 99%

Inhibition of ATP‐sensitive potassium channels by haloperidol

Yang

Proks

Ashcroft

et al. 2004

British J Pharmacology

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1 Chronic haloperidol treatment has been associated with an increased incidence of glucose intolerance and type-II diabetes mellitus. We studied the effects of haloperidol on native ATP-sensitive potassium (K ATP ) channels in mouse pancreatic b cells and on cloned Kir6.2/SUR1 channels expressed in HEK293 cells. 2 The inhibitory effect of haloperidol on the K ATP channel was not mediated via the D2 receptor signaling pathway, as both D2 agonists and antagonists blocked the channel. 3 K ATP currents were studied using the patch-clamp technique in whole-cell and outside-out patch configurations. Addition of haloperidol to the extracellular solution inhibited the K ATP conductance immediately, in a reversible and voltage-independent manner. Haloperidol did not block the channel when applied intracellularly in whole-cell recordings. 4 Haloperidol blocked cloned Kir6.2/SUR1 and Kir6.2DC36 K ATP channels expressed in HEK cells. This suggests that the drug interacts with the Kir6.2 subunit of the channel. 5 The IC 50 for inhibition of the K ATP current by haloperidol was 1.6 mM in 2 mM extracellular K þ concentration ([K þ ] o ) and increased to 23.9 mM in 150 mM [K þ ] o . The Hill coefficient was close to unity, suggesting that the binding of a single molecule of haloperidol is sufficient to close the channel. 6 Haloperidol block of K ATP channels may contribute to the side effects of this drug when used therapeutically.

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Section: Voltage Dependency Of Haloperidol Blockagementioning

confidence: 99%

Inhibition of ATP‐sensitive potassium channels by haloperidol

Yang

Proks

Ashcroft

et al. 2004

British J Pharmacology

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“…Haloperidol, has been shown to block this channel expressed in Xenopus oocytes in a concentration-dependent manner with an IC 50 of 1 mM. 8 Despite the clear ability of haloperidol to bring about relevant changes in ion channel activity in vitro and a number of incriminating case reports of cardiotoxicity, 9 the ability of therapeutic doses of haloperidol to prolong the QT c interval in healthy subjects without the presence of interacting drugs is not known.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and QT interval pharmacodynamics of oral haloperidol in poor and extensive metabolizers of CYP2D6

Desai

Tanus‐Santos

et al. 2003

Pharmacogenomics J

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We studied the pharmacokinetics and QT interval pharmacodynamics of a single 10 mg dose of oral haloperidol in a randomized, double-blind, placebo-controlled, crossover trial of healthy poor (PMs) and extensive (EMs) metabolizers of CYP2D6. There was a statistically significant greater mean QT c on haloperidol (421.6720.1 ms) than on placebo (408.4718.5 ms, P ¼ 0.0053) occurring 10 h post haloperidol/placebo administration. Men and women had similar ranges of QT c changes from placebo. Despite a statistically significant greater mean elimination half-life (19.173.6 vs 12.974.0 h, P ¼ 0.04) and lower mean apparent oral clearance (12.874.1 vs 27.0711.3 ml/min/kg, P ¼ 0.02) of haloperidol in CYP2D6 PMs than in EMs, this exposure change did not translate into marked QT c changes from baseline that could be considered clinically important. Although the magnitude of the mean QT c prolongation on haloperidol relative to placebo is relatively small, it may assume significance in the presence of other risk factors for QT prolongation. The Pharmacogenomics Journal (2003) 3, 105-113. doi:10.1038/sj.tpj.6500160Keywords: haloperidol; CYP2D6 genotype; QT INTRODUCTION Schizophrenia is a common psychiatric disease with a lifetime prevalence of nearly 1% of the general population 1 that is associated with an increased risk of premature death. A recent meta-analysis revealed that schizophrenic patients are 1.5 times more likely of dying from all causes compared to an age-and gendermatched cohort of the general population. 2 While it is not known how much of this excess risk can be attributed to antipsychotic-induced cardiotoxicity, it is clear that many antipsychotics are arrhythmogenic. 3 Among the antipsychotic drugs, haloperidol remains one of the most widely used worldwide. Haloperidol-induced ventricular arrhythmias of the torsades de pointes (TdP) type have been reported with a range of doses starting as low as 4 mg 4 administered over a 24 h period and as high as 825 mg 5 over a 24-h period. Cardiac side effects at high doses likely involve excessive exposure to haloperidol. However, the extent to which low doses of haloperidol contribute to QT interval prolongation in the absence of risk factors 6 such as age, concomitant medications, electrolyte imbalances, ischemic heart disease, or congenitally prolonged QT intervals is less well characterized. Prolongation of the QT interval is a biomarker for the malignant ventricular arrhythmia of TdP.In vitro cardiac electrophysiology studies that we have conducted demonstrate that supratherapeutic concentrations of haloperidol prolong the heart rate corrected QT interval (QT c ) by approximately 26% in an isolated perfused feline heart model. 7 The mechanism of haloperidol-mediated QT prolongation

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“…It is of importance to mention that the human ether-à-gogo -related gene ( HERG ) has also been found to be primarily responsible for this type of K ϩ current (Sanguinetti et al 1995) and that haloperidol can block HERG channel expressed in frog oocytes (Suessbrich et al 1997). Taken together, the possibility has arisen that in addition to their effects on the bindings to the receptors, the neuroleptic agents might be the regulators of ionic channels.…”

mentioning

confidence: 99%

Characterization of Inhibition by Risperidone of the Inwardly Rectifying K+ Current in Pituitary GH3 Cells

Jan

et al. 2000

Neuropsychopharmacology

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The inhibitory effect of the antipsychotic drug haloperidol on HERG potassium channels expressed in Xenopus oocytes

Cited by 215 publications

References 31 publications

Inhibition of ATP‐sensitive potassium channels by haloperidol

Inhibition of ATP‐sensitive potassium channels by haloperidol

Pharmacokinetics and QT interval pharmacodynamics of oral haloperidol in poor and extensive metabolizers of CYP2D6

Characterization of Inhibition by Risperidone of the Inwardly Rectifying K+ Current in Pituitary GH3 Cells

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