Receptor regulation, competitive antagonism and pA2

A growing body of evidence suggests that the number of drug receptors on cell surfaces is not fixed, but is dynamically regulated by circumstances that include exposure to the ligand itself. Because most traditional theories of drug action are based on the assumption of a fixed number of receptors, it is desirable to examine the importance of this regulatory process on the interpretation of dose-effect data. Of special interest is the impact of a variable receptor number on the equation of competitive antagonism and associated pA2 which, in the traditional theory, is a quantitative measure of antagonist-receptor affinity. Using a simple model of drug-induced endocytosis or exocytosis, it is shown that if the rate of either is appreciable, the pA2 is no longer a simple measure of affinity.