Pharmacokinetic-pharmacodynamic modeling: time-dependent protein binding--an alternative interpretation of clockwise and counterclockwise hysteresis.

Development of effect compartment model theory has greatly enhanced our understanding of the relationship between pharmacokinetics and pharmacodynamics. When effect versus concentration in serum (usually total concentration) is plotted and counterclockwise hysteresis is observed, an initial disequilibrium between receptor(s) and serum is generally presumed and an effect compartment model is used; alternatively, clockwise hysteresis may infer tolerance, which may be characterized by an adaptation model. In this simulation study, the influence of time-dependent binding to serum protein on the relationship between effect and concentration in serum was investigated. In these simulations, time-dependent protein binding occurred as a result of an increase in protein concentration in serum or displacement by a metabolite. When concentration of free drug in serum was responsible for the pharmacological response, and response versus total drug concentration in serum was plotted, counterclockwise hysteresis, consistent with an effect compartment, occurred with a time-dependent decrease in binding to serum protein. Clockwise hysteresis, consistent with tolerance, occurred with a time-dependent increase in binding to serum protein. For both sets of simulations, no hysteresis was observed when response was plotted against concentration of free drug in serum. These results indicate that, when response is related to concentration of free drug, measurement of concentration of free drug may allow a clearer interpretation of the pharmacokinetic-pharmacodynamic relationship.