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Research ArticleArticle

Observed Drug-Receptor Association Rates Are Governed by Membrane Affinity: The Importance of Establishing “Micro-Pharmacokinetic/Pharmacodynamic Relationships” at the β2-Adrenoceptor

David A. Sykes, Cheryl Parry, John Reilly, Penny Wright, Robin A. Fairhurst and Steven J. Charlton
Molecular Pharmacology April 2014, 85 (4) 608-617; DOI: https://doi.org/10.1124/mol.113.090209
David A. Sykes
Novartis Institutes for Biomedical Research: Horsham, West Sussex, United Kingdom (D.A.S., C.P., P.W., S.J.C.), Cambridge, Massachusetts (J.R.), and Basel, Switzerland (R.A.F.)
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Cheryl Parry
Novartis Institutes for Biomedical Research: Horsham, West Sussex, United Kingdom (D.A.S., C.P., P.W., S.J.C.), Cambridge, Massachusetts (J.R.), and Basel, Switzerland (R.A.F.)
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John Reilly
Novartis Institutes for Biomedical Research: Horsham, West Sussex, United Kingdom (D.A.S., C.P., P.W., S.J.C.), Cambridge, Massachusetts (J.R.), and Basel, Switzerland (R.A.F.)
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Penny Wright
Novartis Institutes for Biomedical Research: Horsham, West Sussex, United Kingdom (D.A.S., C.P., P.W., S.J.C.), Cambridge, Massachusetts (J.R.), and Basel, Switzerland (R.A.F.)
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Robin A. Fairhurst
Novartis Institutes for Biomedical Research: Horsham, West Sussex, United Kingdom (D.A.S., C.P., P.W., S.J.C.), Cambridge, Massachusetts (J.R.), and Basel, Switzerland (R.A.F.)
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Steven J. Charlton
Novartis Institutes for Biomedical Research: Horsham, West Sussex, United Kingdom (D.A.S., C.P., P.W., S.J.C.), Cambridge, Massachusetts (J.R.), and Basel, Switzerland (R.A.F.)
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Abstract

Current pharmacological models for determining affinity and kinetics of drugs for membrane receptors assume the interacting molecules are homogeneously distributed in the bulk aqueous phase. The phospholipid membrane can, however, provide a second compartment into which drugs can partition, particularly lipophilic/basic compounds. In this study we measured the phospholipid affinity and receptor binding kinetics of several clinically relevant β2-adrenoceptor agonists and antagonists and demonstrated that the degree of phospholipid interaction directly affects the observed kinetic association rate (kon) and dissociation constant (Kd), but not the dissociation rate (koff) from the target, by concentrating drug in the local environment around the receptor. When the local drug concentration was accounted for, the kon was comparable across the cohort and the corrected Kd was directly related to the koff. In conclusion, we propose a new approach to determining the pharmacology of drugs for membrane targets that accounts for differences in local drug concentration brought about by direct affinity for phospholipids, establishing “micro-pharmacokinetic/pharmacodynamic relationships” for drugs.

Footnotes

    • Received October 11, 2013.
    • Accepted January 28, 2014.
  • This work was financed by Novartis Institutes for Biomedical Research.

  • dx.doi.org/10.1124/mol.113.090209.

  • ↵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 (4)
Molecular Pharmacology
Vol. 85, Issue 4
1 Apr 2014
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Research ArticleArticle

Establishing “Micro PK/PD” at the β2-Adrenoceptor

David A. Sykes, Cheryl Parry, John Reilly, Penny Wright, Robin A. Fairhurst and Steven J. Charlton
Molecular Pharmacology April 1, 2014, 85 (4) 608-617; DOI: https://doi.org/10.1124/mol.113.090209

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Research ArticleArticle

Establishing “Micro PK/PD” at the β2-Adrenoceptor

David A. Sykes, Cheryl Parry, John Reilly, Penny Wright, Robin A. Fairhurst and Steven J. Charlton
Molecular Pharmacology April 1, 2014, 85 (4) 608-617; DOI: https://doi.org/10.1124/mol.113.090209
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