On the 'micro'-pharmacodynamic and pharmacokinetic mechanisms that contribute to long-lasting drug action.

Introduction: Optimal drug therapy often requires continuing high levels of target occupancy. Besides the traditional pharmacokinetic (PK) contribution thereto, drug-target interactions that comprise successive 'microscopic' steps as well as the intervention of the cell membrane and other 'micro'-anatomical structures nearby may help attaining this objective.

Areas Covered: This article reviews the 'micro'-pharmacodynamic (PD) and PK mechanisms that may increase a drug's residence time. Special focus is on induced-fit- and bivalent ligand binding models as well as on the ability of the plasma membrane surrounding the target to act as a repository for the drug (e.g., microkinetic model), to actively participate in the binding process (e.g., exosite model) and, along with microanatomical elements like synapses and interstitial spaces, to act on the drug's diffusion properties (reduction in dimensionality and drug-rebinding models).

Expert Opinion: The PK profile, as well as the target dissociation kinetics of a drug, may fail to account for its long-lasting efficiency in intact tissues and in vivo. This lacuna could potentially be alleviated by incorporating some of the enumerated 'microscopic' mechanisms and, to unveil them, dedicated experiments on sufficiently physiologically relevant biological material like cell monolayers can already be implemented early on in the lead optimization process.