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Published on: November 11, 2022
Kinetics of drug interaction with the Kv11.1 potassium channel
Adam P Hill1, Mark J Perrin, Juliane Heide
1Mark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia (A.P.H., J.H., T.J.C., S.A.M., J.I.V.); St. Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales, Australia (A.P.H., J.H., T.J.C., S.A.M., J.I.V.); and Barwon Health, Geelong, Victoria, Australia (M.J.P.).
Abstract:
The Kv11.1 potassium channel is the molecular target for the majority of drugs implicated in acquired long QT syndrome, the most common cause of drug-induced sudden cardiac death, and a common reason for drug restriction or withdrawal from the market. While the IC50 for block of Kv11.1 is commonly used to estimate the risk of acquired long QT syndrome, this approach is crude, and it is widely accepted that the kinetics of drug interactions with the channel are a critical component in understanding their mechanism of action and risk profiles. In this study we report the first directly measured kinetics of block and unblock of Kv11.1 by a QT prolonging drug: the antipsychotic clozapine. Our data show that clozapine binding to Kv11.1 is complex. There are at least two kinetically distinct components to both block and unblock, while the kinetics of unblock are dependent on the dose or duration of drug application. Based on these observations, we have proposed a model incorporating kinetically distinct binding to the open and inactivated states of Kv11.1 that can describe the observed kinetic features of clozapine block and correctly predict the overall affinity and apparent nonstate-dependent interaction of clozapine with Kv11.1. Mechanistic insights into drug block of Kv11.1 gained though detailed kinetic analyses such as this have a potential role in development of drugs targeted to specific channel states to reduce unwanted side effects, as well as in the design of better high-throughput preclinical tests for assessing the proarrhythmic effects of QT prolonging drugs.
Insights
The Kv11.1 potassium channel is targeted by drugs causing long QT syndrome. This study reveals complex, state-dependent binding kinetics for clozapine, improving risk assessment for QT prolonging drugs.
Area of Science:
- Pharmacology
- Molecular Biology
- Cardiology
Background:
- The Kv11.1 potassium channel is a key target for drugs causing acquired long QT syndrome, a major cause of sudden cardiac death.
- Current risk assessment using IC50 values for Kv11.1 block is limited; drug-channel interaction kinetics are crucial for understanding mechanism and risk.
- Drug-induced QT prolongation necessitates market withdrawal or restriction of many medications.
Purpose of the Study:
- To directly measure the kinetics of block and unblock of the Kv11.1 channel by the antipsychotic drug clozapine.
- To develop a mechanistic model that explains the observed kinetic features of clozapine interaction with Kv11.1.
- To provide insights for developing safer drugs and improved preclinical tests for QT prolonging effects.
Main Methods:
- Direct kinetic measurements of clozapine block and unblock on the Kv11.1 channel.
- Analysis of dose- and duration-dependent unblock kinetics.
- Development of a kinetic model incorporating binding to open and inactivated channel states.
Main Results:
- Clozapine binding to Kv11.1 exhibits complex kinetics with at least two distinct components for both block and unblock.
- Unblock kinetics are dependent on clozapine dose and duration of drug application.
- A proposed model accurately describes clozapine's kinetic features and predicts its overall affinity and apparent non-state-dependent interaction.
Conclusions:
- Detailed kinetic analysis of drug-channel interactions is essential for understanding proarrhythmic risk.
- The findings provide a mechanistic basis for clozapine's interaction with Kv11.1, accounting for complex kinetics.
- This research can inform the development of drugs with reduced cardiac side effects and enhance preclinical safety testing.
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