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

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 report we have measured the phospholipid affinity and receptor binding kinetics of several clinically relevant β 2 -adrenoceptor agonists and antagonists and demonstrate that the degree of phospholipid interaction directly affects the observed kinetic association rate (k on ) and affinity (K D ), 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 kon was comparable across the cohort and the corrected K D 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 PK/PD relationships" for drugs.