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Research ArticleArticle

Kinetics of Drug Interaction with the Kv11.1 Potassium Channel

Adam P. Hill, Mark J. Perrin, Juliane Heide, Terence J. Campbell, Stefan A. Mann and Jamie I. Vandenberg
Molecular Pharmacology May 2014, 85 (5) 769-776; DOI: https://doi.org/10.1124/mol.114.091835
Adam P. Hill
Mark 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.)
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Mark J. Perrin
Mark 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.)
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Juliane Heide
Mark 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.)
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Terence J. Campbell
Mark 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.)
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Stefan A. Mann
Mark 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.)
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Jamie I. Vandenberg
Mark 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.)
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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.

Footnotes

    • Received January 16, 2014.
    • Accepted February 28, 2014.
  • This work was supported by project grants from the National Health and Medical Research Council (NHMRC) [Grants #573714 and #1006016]; and a Grant-in-Aid from the National Heart Foundation of Australia [Grant G08S 3689]. M.J.P. was supported by an NHMRC-NHFA Postgraduate Scholarship and Mark Cowley Lidwill Scholarship. A.P.H. is supported by an ARC Future Fellowship. J.I.V. is supported by an NHMRC Senior Research Fellowship.

  • dx.doi.org/10.1124/mol.114.091835.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 85 (5)
Molecular Pharmacology
Vol. 85, Issue 5
1 May 2014
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Research ArticleArticle

Kinetics of Drug-Binding to Kv11.1

Adam P. Hill, Mark J. Perrin, Juliane Heide, Terence J. Campbell, Stefan A. Mann and Jamie I. Vandenberg
Molecular Pharmacology May 1, 2014, 85 (5) 769-776; DOI: https://doi.org/10.1124/mol.114.091835

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Research ArticleArticle

Kinetics of Drug-Binding to Kv11.1

Adam P. Hill, Mark J. Perrin, Juliane Heide, Terence J. Campbell, Stefan A. Mann and Jamie I. Vandenberg
Molecular Pharmacology May 1, 2014, 85 (5) 769-776; DOI: https://doi.org/10.1124/mol.114.091835
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