Observed drug-receptor association rates are governed by membrane affinity: the importance of establishing "micro-pharmacokinetic/pharmacodynamic relationships" at the β2-adrenoceptor

Mol Pharmacol. 2014 Apr;85(4):608-17. doi: 10.1124/mol.113.090209. Epub 2014 Jan 29.

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 (k on) and dissociation constant (Kd), but not the dissociation rate (k off) from the target, by concentrating drug in the local environment around the receptor. When the local drug concentration was accounted for, the k on 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-2 Receptor Agonists / chemistry
  • Adrenergic beta-2 Receptor Agonists / pharmacokinetics
  • Adrenergic beta-2 Receptor Agonists / pharmacology*
  • Adrenergic beta-2 Receptor Antagonists / chemistry
  • Adrenergic beta-2 Receptor Antagonists / pharmacokinetics
  • Adrenergic beta-2 Receptor Antagonists / pharmacology*
  • Animals
  • Binding, Competitive
  • CHO Cells
  • Cell Membrane / metabolism*
  • Cricetinae
  • Cricetulus
  • Humans
  • Ligands
  • Membranes, Artificial
  • Models, Biological*
  • Phospholipids / chemistry
  • Phospholipids / metabolism
  • Radioligand Assay
  • Receptors, Adrenergic, beta-2 / metabolism*

Substances

  • Adrenergic beta-2 Receptor Agonists
  • Adrenergic beta-2 Receptor Antagonists
  • Ligands
  • Membranes, Artificial
  • Phospholipids
  • Receptors, Adrenergic, beta-2