The atypic antipsychotic clozapine inhibits multiple cardiac ion channels
Marguerite Le Marois1, Camille Sanson1, Magali-Anne Maizières1
1High Content Biology, Integrated Drug Discovery, Sanofi-Aventis R&D, 13 quai Jules Guesde, 94403, Vitry-sur-Seine, France.
Abstract:
Clozapine is an atypical neuroleptic used to manage treatment-resistant schizophrenia which is known to inhibit cardiac hERG/KV11.1 potassium channels, a pharmacological property associated with increased risk of potentially fatal Torsades de Pointes (TdP) and sudden cardiac death (SCD). Yet, the long-standing clinical practice of clozapine does not show a consistent association with increased incidence of TdP, although SCD is considerably higher among schizophrenic patients than in the general population. Here, we have established the inhibitory profile of clozapine at the seven cardiac ion currents proposed by the ongoing comprehensive in vitro pro-arrhythmia (CiPA) initiative to better predict new drug cardio-safety risk. We found that clozapine inhibited all CiPA currents tested with the following rank order of potency: KV11.1 > NaV1.5 (late current) ≈ CaV1.2 ≈ NaV1.5 (peak current) ≈ KV7.1 > KV4.3 > Kir2.1 (outward current). Half-maximal inhibitory concentrations (IC50) at the repolarizing KV11.1 and KV7.1 channels, and at the depolarizing CaV1.2 and NaV1.5 channels fell within a narrow half-log 3-10 µM concentration range, suggesting that mutual compensation could explain the satisfactory arrhythmogenic cardio-safety profile of clozapine. Although the IC50 values determined herein using an automated patch-clamp (APC) technique are at the higher end of clozapine plasmatic concentrations at target therapeutic doses, this effective antipsychotic appears prone to distribute preferentially into the cardiac tissue, which supports the clinical relevance of our in vitro pharmacological findings.
Insights
Clozapine inhibits cardiac ion channels, but its clinical safety suggests a complex interaction. This study reveals clozapine
Area of Science:
- Pharmacology
- Cardiology
- Neuroscience
Background:
- Clozapine, an atypical neuroleptic for treatment-resistant schizophrenia, inhibits cardiac hERG/KV11.1 channels, linked to Torsades de Pointes (TdP) and sudden cardiac death (SCD).
- Despite known hERG inhibition, clozapine's clinical use shows a paradoxical lack of consistent TdP association, though SCD remains elevated in schizophrenia patients.
- The Comprehensive in vitro Pro-arrhythmia (CiPA) initiative aims to improve cardiac safety risk prediction for new drugs.
Purpose of the Study:
- To characterize the inhibitory profile of clozapine across seven cardiac ion currents.
- To elucidate the mechanisms underlying clozapine's arrhythmogenic cardio-safety profile.
- To assess the clinical relevance of in vitro findings regarding clozapine's cardiac effects.
Main Methods:
- Automated patch-clamp (APC) technique was employed to determine clozapine's inhibitory concentrations.
- Clozapine's inhibitory effects were evaluated across seven cardiac ion currents, including KV11.1, NaV1.5, CaV1.2, KV7.1, KV4.3, and Kir2.1.
- Half-maximal inhibitory concentrations (IC50) were measured for each inhibited current.
Main Results:
- Clozapine inhibited all tested CiPA currents, with a potency rank order: KV11.1 > NaV1.5 (late) ≈ CaV1.2 ≈ NaV1.5 (peak) ≈ KV7.1 > KV4.3 > Kir2.1 (outward).
- IC50 values for repolarizing (KV11.1, KV7.1) and depolarizing (CaV1.2, NaV1.5) channels were within a narrow 3-10 µM range.
- These IC50 values, though at the higher end of therapeutic plasma concentrations, suggest preferential distribution into cardiac tissue.
Conclusions:
- Mutual compensation among inhibited cardiac ion channels may explain clozapine's satisfactory arrhythmogenic cardio-safety profile.
- Clozapine's preferential distribution to cardiac tissue supports the clinical relevance of its in vitro ion channel inhibition profile.
- These findings contribute to a better understanding of clozapine's cardiac safety and inform future drug development using the CiPA initiative.
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