Abstract

A pharmacokinetic model was constructed to explain the difference in brain- and cerebrospinal fluid (CSF)-to-plasma and brain-to-CSF unbound drug concentration ratios (K_p,uu,brain, K_p,uu,CSF, and K_{p,uu,CSF/brain}, respectively) of drugs under steady-state conditions in rats. The passive permeability across the blood-brain barrier (BBB), PS₁, was predicted by two methods using log(D/molecular weight^0.5) for PS₁(1) or the partition coefficient in octanol/water at pH 7.4 (LogD), topologic van der Waals polar surface area, and van der Waals surface area of the basic atoms for PS₁(2). The coefficients of each parameter were determined using previously reported in situ rat BBB permeability. Active transport of drugs by P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) measured in P-gp- and Bcrp-overexpressing cells was extrapolated to in vivo by introducing scaling factors. Brain- and CSF-to-plasma unbound concentration ratios (K_p,uu,brain and K_p,uu,CSF, respectively) of 19 compounds, including P-gp and Bcrp substrates (daidzein, dantrolene, flavopiridol, genistein, loperamide, quinidine, and verapamil), were simultaneously fitted to the equations in a three-compartment model comprising blood, brain, and CSF compartments. The calculated K_p,uu,brain and K_p,uu,CSF of 17 compounds were within a factor of three of experimental values. K_p,uu,CSF values of genistein and loperamide were outliers of the prediction, and K_p,uu,brain of dantrolene also became an outlier when PS₁(2) was used. K_{p,uu,CSF/brain} of the 19 compounds was within a factor of three of experimental values. In conclusion, the K_{p,uu,CSF/brain} of drugs, including P-gp and Bcrp substrates, could be successfully explained by a kinetic model using scaling factors combined with in vitro evaluation of P-gp and Bcrp activities.