Brain-to-Plasma Concentration Ratio and Unbound Partition Coefficient

Abstract

The brain-to-plasma concentration ratio (or totalbrain-to-plasma ratio, or simply, brain-to-plasma ratio, Kp, also referred toas B/P ratio or BB) is, as suggested by the name, the ratio between the total(bound and unbound) brain concentration Cbrain,ss and the total blood concentrationCblood.ss, at (pseudo)distribution equilibrium (steady state):Kp=Cbrain,ssCblood,ss(1) Kp has been extensively used atpreclinical drug development as an index of blood-brain barrier permeabilityand central nervous system (CNS) exposure. Alternatively to Eq. 1, it can alsobe computed as: Kp=AUCbrain,ssAUCblood,ss (2), where AUCbrain,ss denotes thearea under the curve of total concentrations in the brain (at steady state) andAUCblood,ss represents the area under the curve of total concentrations inblood (also at steady state). Often, Kp has been measured based on a crudehomogenization of brain tissue. Despite how tempting it may be to guidecompound optimization applying rapid in vitro assays, there is currentconsensus that the unbound brain-to-plasma ratio Kp,uu is much more relevant(or biorelevant) from a pharmacological perspective, as this parameter oftenshows a better correlation with receptor occupancy and other pharmacodynamicreadouts. This is because the magnitude of a pharmacological effect typicallydepends on the unbound (or free) drug levels in the biophase, and not on thetotal drug concentration. Since Kp is heavily influenced by nonspecificbinding, the efforts to optimize this parameter may in fact lead to anunproductive or even counterproductive design of drugs that have a high degreeof nonspecific (and pharmacodynamically inert) partitioning into brain tissue.