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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on April 3, 2007; DOI: 10.1124/jpet.107.121525

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Received for publication February 16, 2007.
Revised April 1, 2007.
Accepted for publication April 2, 2007.

CNS Drug Disposition: The Relationship Between In Situ Brain Permeability and Brain Free Fraction

Scott Graham Summerfield 1*, Kevin D. Read 1, David J. Begley 2, Tanja T. Obradovic 3, Ismael J. Hidalgo 3, Sara Coggon 4, Ann V. Lewis 1, Rod A. Porter 1, Phillip Jeffrey 1

1 GlaxoSmithKline Pharmaceuticals 2 King's College London 3 Absorption Systems 4 UCB Celltech

* Address correspondence to: E-mail: scott.g.summerfield{at}gsk.com

Abstract

The dispositions of 50 marketed CNS drugs into the brain have been examined in terms of their rat in situ permeability (P) and in vitro permeability (Papp) alongside lipophilicity and free fraction in rat brain tissue. The interrelationship between these parameters highlights that both permeability and brain tissue binding influence the uptake of drugs into the CNS. Hydrophilic compounds characterised by low brain tissue binding display a strong correlation (R2 = 0.82) between P and Papp, whereas the uptake of more lipophilic compounds appears to be influenced by both Papp and brain free fraction. A non-linear relationship is observed between logPoct and P over the 6 orders of magnitude range in lipophilicity studied. These findings corroborate recent reports in the literature that brain penetration is a function of both rate and extent of drug uptake into the CNS.


Key words: blood-brain barrier, brain, equilibrium dialysis, free-fraction, lipophilicity, permeability


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