Mixture dynamics: Dual action of inhibition and stimulation

The impact of a drug, or of multiple drugs, on different receptors usually results in a combination of responses. They may be either opposing or reinforcing one another and can lead to complex response versus drug-concentration relations. In this paper, complexity and synergy of multiple drug actions are studied on the basis of four data sets: two involving opposing actions and two resulting from synergistic actions. It is shown that turnover models can be successfully fitted to these data, offer a mechanism for dissecting complex response versus drug-concentration curves, for understanding and quantifying amplification of dual drug actions and elucidate the role of potencies and other parameters related to the different drugs.

Schematic diagram of the modeling approach: Data are collected and plotted. A suite of models that capture the response-time courses are suggested. Models are then fitted to the data. The equilibrium concentration-response relationship is derived and simulated.119