Investigation of a cellular pharmacodynamic model exhibiting sharp response sensitivity and tolerance

The potential relevance of a kinetic model for switch-like behavior in biochemical reactions to pharmacodynamics is explored. This model, which postulates that drug acts by modulating the balance of kinase and phosphatase activities, and their effect on the phosphorylation state of an effector molecule critical in determining drug effect, predicts sharp concentration-effect profiles without explicit incorporation of cooperativity. The degree of sharpness depends on concentration of the critical effector. It is argued that such a model can account for inter-individual differences in pharmacodynamic sensitivity profiles, as well as intra-individual changes in sensitivity associated with time-varying physiological processes or disease. By augmenting the model with a kinetic description of critical effector synthesis and degradation in the nonphosphorylated and phosphorylated forms, a putative mechanism for drug tolerance is revealed. The combined model predicts that tolerance, in addition to attenuating the maximum effect, may lead to a decrease in apparent Hill coefficient.