The inverse relationship between drug affinity and effectiveness: prediction under rate theory, paradox under...

The two major theories of drug action are occupancy theory and rate theory. Although the two theories make a number of predictions that should serve to clearly distinguish one from the other, data generated over the last 25 years in intact muscle or organ systems have failed in this respect because the interpretation of those data has been confounded by unknown and unmeasurable factors such as the rates and extent of drug diffusion, uptake and metabolism. In the present communication rate theory and occupancy theory are discussed in the light of data obtained from a broken-cell system in which uncontrollable factors are minimized, the beta adrenergic-responsive adenylate cyclase of the S49 mouse lymphoma cell line. It is pointed out that rate theory predicts an inverse relationship between the affinity of isoproterenol (INE) for the beta adrenergic receptor and the magnitude of stimulation of adenylate cyclase. On the other hand, occupancy theory predicts that the affinity of INE and the magnitude of its effect will be directly related. By fitting data obtained in this system to the simple equations derived from the two theories it is demonstrated that the available data are in excellent agreement with the predictions of rate theory and diametrically opposed to the predictions of occupancy theory.