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First published on February 24, 2006; DOI: 10.1124/dmd.105.007914

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Received for publication October 19, 2005.
Revised February 13, 2006.
Accepted for publication February 15, 2006.

Evaluation of the Utility of Brain Slice Methods to Study Brain Penetration

Xingrong Liu 1* Stacey Becker 1

1 Pfizer Global Research and Development

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

Abstract

The objective of this study was to evaluate the utility of brain tissue slices to determine the effect of plasma and brain tissue nonspecific binding on the brain-to-plasma ratio (Kp). Mouse or rat brain slices (400 µm) were prepared using a McIlwain tissue chopper and incubated with 1 µg/mL of substrate at 37oC either in a physiological buffer to determine the buffer-to-slice concentration ratio, i.e. unbound fraction in brain tissue (fu,slice) or in plasma to determine the slice-to-plasma concentration ratio (Cslice/Cplasma). The unbound fraction in plasma, fu,plasma was determined using equilibrium dialysis. In vitro-in vivo correlation of the brain-to-plasma ratio was examined for thirteen and eight model compounds in mice and rats, respectively. Cslice/Cplasma and fu,plasma/fu,slice predicted the Kp in rats and Cslice/Cplasma predicted the Kp in FVB mice for non-P-glycoprotein substrates within 3-fold but over predicted Kp for P-glycoprotein substrates by more than 3-fold. However, Cslice/Cplasma predicted the Kp in mdr1a/1b knockout mice for both non-P-glycoprotein and P-glycoprotein substrates. Our present study demonstrates that a brain slice method can be used to differentiate whether a compound having a low Kp is due to the effect of low nonspecific binding to brain tissue relative to plasma proteins or due to efflux transport at the blood-brain barrier.


Key words: blood-brain barrier, blood-CNS transport, CNS pharmacokinetics, drug development, drug discovery, drug disposition, drug distribution


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