A major challenge associated with the determination of the unbound brain-to-plasma concentration ratio of a drug (K(p,uu,brain)), is the error associated with correction for the drug in various vascular spaces of the brain, i.e., in residual blood. The apparent brain vascular spaces of plasma water (V(water), 10.3 microL/g brain), plasma proteins (V(protein), 7.99 microL/g brain), and the volume of erythrocytes (V(er), 2.13 microL/g brain) were determined and incorporated into a novel, drug-specific correction model that took the drug-unbound fraction in the plasma (f(u,p)) into account. The correction model was successfully applied for the determination of K(p,uu,brain) for indomethacin, loperamide, and moxalactam, which had potential problems associated with correction. The influence on correction of the drug associated with erythrocytes was shown to be minimal. Therefore, it is proposed that correction for residual blood can be performed using an effective plasma space in the brain (V(eff)), which is calculated from the measured f(u,p) of the particular drug as well as from the estimates of V(water) and V(protein), which are provided in this study. Furthermore, the results highlight the value of determining K(p,uu,brain) with statistical precision to enable appropriate interpretation of brain exposure for drugs that appear to be restricted to the brain vascular spaces.