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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on March 2, 2005; DOI: 10.1124/jpet.104.079319

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Received for publication October 19, 2004.
Revised February 24, 2005.
Accepted for publication February 28, 2005.

Use of a Physiologically Based Pharmacokinetic Model to Study the Time to Reach Brain Equilibrium: An Experimental Analysis of the Role of Blood-Brain Barrier Permeability, Plasma Protein Binding, and Brain Tissue Binding

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

1 Pfizer Global Research and Development

* Address correspondence to: E-mail: xingrong_liu{at}groton.pfizer.com

Abstract

This study was designed (1) to examine the effects of blood-brain barrier (BBB) permeability (quantified as permeability-surface area product, PS), unbound fraction in plasma (fu,plasma) and brain tissue (fu,brain) on the time to reach equilibrium between brain and plasma and (2) to investigate the drug discovery strategies to design and select compounds that can rapidly penetrate the BBB and distribute to the site of action. The pharmacokinetics of seven model compounds: caffeine, CP-141938, fluoxetine, NFPS, propranolol, theobromine, and theophylline in rat brain and plasma after subcutaneous administration was studied. The in vivo logPS and logfu,brain calculated using a physiologically based pharmacokinetic model correlates with in situ logPS (R2 = 0.83) and in vitro logfu,brain (R2 = 0.69), where the in situ PS and in vitro fu,brain was determined using in situ brain perfusion and equilibrium dialysis using brain homogenate, respectively. The time to achieve brain equilibrium can be quantitated with a proposed parameter, intrinsic brain equilibrium half-life [t1/2eq,in = Vbln2/(PS·fu,brain), where Vb is the physiological volume of brain). The in vivo logt1/2eq,in does not correlate with in situ logPS (R2 < 0.01) but correlates inversely with log(PS·fu,brain) (R2 = 0.85). The present study demonstrates that rapid brain equilibration requires a combination of high BBB permeability and low brain tissue binding. A high BBB permeability alone cannot guarantee a rapid equilibration. The strategy to select compounds with rapid brain equilibration in drug discovery should identify compounds with high BBB permeability and low nonspecific binding in brain tissue.


Key words: blood-brain barrier, brain penetration, drug discovery, nonspecific binding, permeability, pharmacokinetics


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