title: On the 'micro'-pharmacodynamic and pharmacokinetic mechanisms that contribute to long-lasting drug action.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: a Free University Brussels (VUB), Molecular and Biochemical Pharmacology Department , Pleinlaan 2, B-1050 Brussels, Belgium +32 2 6291955 ; +32 2 6291358 ; gvauquel@vub.ac.be.
authors.forename: Georges
authors.initials: G
authors.lastname: Vauquelin
mesh_terms: D002462:Cell Membrane / Q000378:metabolism; D004058:Diffusion; D016503:Drug Delivery Systems; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000378:metabolism; D010599:Pharmacokinetics; D013569:Synapses / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D008024:Ligands; D004364:Pharmaceutical Preparations
keywords: binding mechanisms; diffusion; drug target; membrane; pharmacodynamics; pharmacokinetics; radioligand; rebinding; receptor; residence time