Rebinding: or why drugs may act longer in vivo than expected from their in vitro target residence time

Abstract

Importance of the field: It is well established that the in vivo duration of drug action not only depends on macroscopic pharmacokinetic properties like its plasma half-life, but also on the residence time of the drug–target complexes. However, drug ‘rebinding’ (i.e., the consecutive binding of dissociated drug molecules to the original target and/or targets nearby) can be influential in vivo as well.

Areas covered in this review: Information about rebinding is available since the 1980s but it is dispersed in the life sciences literature. This review compiles this information. In this respect, neurochemists and biopohysicians advance the same equations to describe drug rebinding.

What the reader will gain: The rebinding mechanism is explained according to the prevailing viewpoint in different life science disciplines. There is a general consensus that high target densities, high association rates and local phenomena that hinder the diffusion of free drug molecules away from their target all promote rebinding.

Take home message: Simulations presented here for the first time suggest that rebinding may increase the duration and even the constancy of the drug's clinical action. Intact cell radioligand dissociation and related ex vivo experiments offer useful indications about a drug's aptitude to experience target rebinding.

Keywords::

• cell lines
• diffusion
• drug–target binding
• pharmacokinetics
• radioligand
• rebinding
• receptors
• residence time
• simulations
• synapses

Notes

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