Observed drug-receptor association rates are governed by membrane affinity: The importance of establishing "micro-pharmacokinetic/pharmacodynamic relationships" at the ?2-adrenoceptor

Sykes, David A.; Parry, Cheryl; Reilly, John; Wright, Penny; Fairhurst, Robin A.; Charlton, Steven J.

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 ?2-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 k off. 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.

• Journal Article Type: Article
• Acceptance Date: Jan 28, 2014
• Online Publication Date: Feb 21, 2014
• Publication Date: Apr 1, 2014
• Deposit Date: Mar 16, 2018
• Journal: Molecular Pharmacology
• Print ISSN: 0026-895X
• Electronic ISSN: 1521-0111
• Publisher: American Society for Pharmacology and Experimental Therapeutics
• Peer Reviewed: Peer Reviewed
• Volume: 85
• Issue: 4
• Pages: 608-617
• DOI: https://doi.org/10.1124/mol.113.090209
• Keywords: Molecular Medicine; Pharmacology
• Public URL: https://nottingham-repository.worktribe.com/output/1109907
• Publisher URL: http://molpharm.aspetjournals.org/content/85/4/608
• PMID: 00033286