Evaluation of cerebrospinal fluid concentration and plasma free concentration as a surrogate measurement for brain free concentration

This study was designed to evaluate the use of cerebrospinal fluid (CSF) drug concentration and plasma unbound concentration (C-u,C-plasma) to predict brain unbound concentration (C-u,C-brain). The concentration-time profiles in CSF, plasma, and brain of seven model compounds were determined after subcutaneous administration in rats. The Cu, brain was estimated from the product of total brain concentrations and unbound fractions, which were determined using brain tissue slice and brain homogenate methods. For theobromine, theophylline, caffeine, fluoxetine, and propranolol, which represent rapid brain penetration compounds with a simple diffusion mechanism, the ratios of the area under the curve of C-u,C-brain/C-CSF and C-u,C-brain/C-u,C-plasma were 0.27 to 1.5 and 0.29 to 2.1, respectively, using the brain slice method, and were 0.27 to 2.9 and 0.36 to 3.9, respectively, using the brain homogenate method. A P-glycoprotein substrate, CP-141938 (methoxy-3-[(2-phenylpiperadinyl-3-amino)-methyl]-phenyl-N-methyl-methane-sulfonamide), had C-u,C-brain/C-CSF and C-u,C-brain/C-u,C-plasma ratios of 0.57 and 0.066, using the brain slice method, and 1.1 and 0.13, using the brain homogenate method, respectively. The slow brain-penetrating compound, N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl] sarcosine, had C-u,C-brain/C-CSF and C-u,C-brain/C-u,C-plasma ratios of 0.94 and 0.12 using the brain slice method and 0.15 and 0.018 using the brain homogenate method, respectively. Therefore, for quick brain penetration with simple diffusion mechanism compounds, C-CSF and C-u,C-plasma represent C-u,C-brain equally well; for efflux substrates or slow brain penetration compounds, C-CSF appears to be equivalent to or more accurate than C-u,C-plasma to represent C-u,C-brain. Thus, we hypothesize that C-CSF is equivalent to or better than C-u,C-plasma to predict C-u,C-brain. This hypothesis is supported by the literature data.