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Drug Metabolism and Disposition Fast Forward
First published on June 7, 2006; DOI: 10.1124/dmd.105.008201

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Received for publication November 4, 2005.
Revised May 12, 2006.
Accepted for publication May 23, 2006.

EVALUATION OF CEREBROSPINAL FLUID CONCENTRATION AND PLASMA FREE CONCENTRATION AS A SURROGATE MEASUREMENT FOR BRAIN FREE CONCENTRATION

Xingrong Liu 1*, Bill J Smith 1, Cuiping Chen 2, Ernesto Callegari 2, Stacey L Becker 2, Xi Chen 2, Julie Cianfrogna 2, Angela C Doran 2, Shawn D Doran 2, John P Gibbs 2, Natilie Hosea 2, Jianhua Liu 2, Frederick R Nelson 2, Mark A Szewc 2, Jeffrey Van Deusen 2

1 Pfizer Global Research and Development 2 Pfizer Global R&D

* Address correspondence to: E-mail: xingrongliu2000{at}yahoo.com

Abstract

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 following 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 (AUC) of Cu,brain andCCSF and Cu,brain/Cu,plasma were 0.27-1.5 and 0.29-2.1, respectively, using brain slice method and were 0.27-2.9 and 0.36-3.9, respectively, using brain homogenate method. P-glycoprotein substrate, CP-141938, had Cu,brain/CCSF and Cu,brain andCu,plasma ratios of 0.57 and 0.066, respectively. The slow brain penetrating compound, NFPS, 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 a 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.


Key words: blood-brain barrier, blood-CNS transport, CNS pharmacokinetics, drug delivery, drug development, drug discovery, plasma protein binding


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