Observed Drug-Receptor Association Rates Are Governed by Membrane Affinity: The Importance of Establishing “Micro-Pharmacokinetic/Pharmacodynamic Relationships” at the b2-Adrenoceptor s

Current pharmacological models for determining affinity and kinetics of drugs for membrane receptors assume the interact-ing 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 mea-sured the phospholipid affinity and receptor binding kinetics of several clinically relevant b2-adrenoceptor agonists and antag-onists and demonstrated that the degree of phospholipid inter-action 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 phospho-lipids, establishing “micro-pharmacokinetic/pharmacodynamic relationships ” for drugs