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 (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 k_on 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-pharmacokinetic/pharmacodynamic relationships” for drugs.