The importance of plasma protein binding in drug discovery

Abstract

Plasma protein binding of drugs is a well-recognised phenomena, but it is only recently that the implications for drug action in vivo have been fully appreciated. Plasma proteins, by virtue of their high concentration, control the free drug concentration in plasma and in compartments in equilibrium with plasma, thereby, effectively attenuating drug potency in vivo. The historical background and thermodynamic basis for the ‘Free Drug Principle’ is presented, along with special considerations for intracellular targets, deep compartments and α₁-acid glycoprotein binding. Real and apparent exceptions to the principle are discussed along with a survey of citations from the recent medicinal chemistry literature.

Keywords::

• α₁-acid glycoprotein
• albumin
• brain:plasma ratio
• equilibrium dialysis
• Free Drug Principle
• free fraction
• microdialysis
• plasma protein binding
• shift assay
• unbound fraction

Acknowledgements

The assistance of B Galione in the preparation of this manuscript is gratefully acknowledged by the author. N Meanwell and B Washburn are thanked for their critical reading and suggestions. Finally, S Grossman and D Christ are thanked for many stimulating discussions on the topic of plasma protein binding and for facilitating the experimental work in this area.