Unbound brain-to-plasma partition coefficient determination

Abstract

The unbound brain-to-plasma concentration ratio (or unboundbrain-to-plasma ratio, Kp,uu) reflects the partition of unbound drug betweenthe brain and the plasma, at steady state.where Cu,brain,ss is the unbounddrug concentration in the brain, at steady state, and Cu,blood,ss is the unbunddrug concentration in blood, at steady state. It is a critical parameterto evaluate if the distribution (pseudo)equilibrium between blood and braincompartments has been achieved, reflecting the joint impact of passivepermeability and transporters at the blood-brain barrier. Furthermore, it doesnot depend on protein binding in blood or binding to brain tissue constituents.(the bound fraction in blood and the brain is pharmacologically inert; theunbound or free fraction, in contrast, is able to diffuse trough physiologicalbarriers and engage with the target). As the unbound fraction is more relevantfrom a pharmacological viewpoint, Kp,uu is at present considered one of themost relevant parameters to guide the selection and optimization of centralnervous system (CNS) drug candidates (usually preferring compounds withcomparatively high Kp,uu values). Contrariwise, it may also be used during thescreening of peripheral drugs, since minimizing unbound exposure in the brainmight reduce the incidence of central side effects. Microdialysis is currentlythe gold standard for Kp,uu determinations, although other less complextechniques with better throughput have also been proposed. Also, in silicomethods for Kp,uu estimation have increasingly appeared in the specializedliterature.