Brain-to-Plasma Concentration Ratio and Unbound Partition Coefficient

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The unbound brain-to-plasma concentration ratio (or unbound brain-to-plasma ratio, Kp,uu) reflects the partition of unbound drug between the brain and the plasma, at steady state: K_(p,uu)=C_(u,brain,ss)/C_(u,blood,ss) (1)It is a critical parameter to evaluate if the distribution (pseudo)equilibrium between blood and brain compartments has been achieved, reflecting the joint impact of passive permeability and transporters at the blood-brain barrier [1]. Furthermore, it does not depend on protein binding in blood or binding to brain tissue constituents [2] (the bound fraction in blood and brain is pharmacologically ?inert?; the unbound or free fraction, in contrast, is able to diffuse trough physiological barriers and engage with the target [3]). As the unbound fraction is the more relevant from a pharmacological viewpoint, Kp,uu is now considered one of the most relevant parameters to guide the selection and optimization of central nervous system (CNS) drug candidates (usually preferring compounds with comparatively high Kp,uu values). Contrarywise, it may also be used during the screening of peripheral drugs, since minimizing unbound exposure in the brain might reduce the incidence of central side effects [4]. Microdialysis is currently the gold standard for Kp,uu determinations, although other less complex techniques with better throughput have also been proposed. Also, in silico methods for Kp,uu estimation have increasingly appeared in the specialized literature. Información suministrada por el agente en SIGEVA