PT - JOURNAL ARTICLE AU - Xingrong Liu AU - Bill J. Smith AU - Cuiping Chen AU - Ernesto Callegari AU - Stacey L. Becker AU - Xi Chen AU - Julie Cianfrogna AU - Angela C. Doran AU - Shawn D. Doran AU - John P. Gibbs AU - Natilie Hosea AU - Jianhua Liu AU - Frederick R. Nelson AU - Mark A. Szewc AU - Jeffrey Van Deusen TI - Evaluation of Cerebrospinal Fluid Concentration and Plasma Free Concentration As a Surrogate Measurement for Brain Free Concentration AID - 10.1124/dmd.105.008201 DP - 2006 Sep 01 TA - Drug Metabolism and Disposition PG - 1443--1447 VI - 34 IP - 9 4099 - http://dmd.aspetjournals.org/content/34/9/1443.short 4100 - http://dmd.aspetjournals.org/content/34/9/1443.full SO - Drug Metab Dispos2006 Sep 01; 34 AB - This study was designed to evaluate the use of cerebrospinal fluid (CSF) drug concentration and plasma unbound concentration (Cu,plasma) to predict brain unbound concentration (Cu,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 Cu,brain/CCSF and Cu,brain/Cu,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-phenyl-piperadinyl-3-amino)-methyl]-phenyl-N-methyl-methane-sulfonamide), had Cu,brain/CCSF and Cu,brain/Cu,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 Cu,brain/CCSF and Cu,brain/Cu,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, CCSF and Cu,plasma represent Cu,brain equally well; for efflux substrates or slow brain penetration compounds, CCSF appears to be equivalent to or more accurate than Cu,plasma to represent Cu,brain. Thus, we hypothesize that CCSF is equivalent to or better than Cu,plasma to predict Cu,brain. This hypothesis is supported by the literature data. The American Society for Pharmacology and Experimental Therapeutics