Free Drug Theory - No Longer Just a Hypothesis?

The Free Drug Hypothesis is a well-established concept within the scientific lexicon pervading many areas of Drug Discovery and Development, and yet it is poorly defined by virtue of many variations appearing in the literature. Clearly, unbound drug is in dynamic equilibrium with respect to absorption, distribution, metabolism, elimination, and indeed, interaction with the desired pharmacological target. Binding interactions be they specific (e.g. high affinity) or nonspecific (e.g. lower affinity/higher capacity) are governed by the same fundamental physicochemical tenets including Hill-Langmuir Isotherms, the Law of Mass Action and Drug Receptor Theory. With this in mind, it is time to recognise a more coherent version and consider it the Free Drug Theory and a hypothesis no longer. Today, we have the experimental and modelling capabilities, pharmacological knowledge, and an improved understanding of unbound drug distribution (e.g. Kp_uu) to raise the bar on our understanding and analysis of experimental data. The burden of proof should be to rule out mechanistic possibilities and/or experimental error before jumping to the conclusion that any observations contradict these fundamentals.