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Pharmaceutics 2014, 6(1), 97-136; doi:10.3390/pharmaceutics6010097
Article

Development of a Physiologically-Based Pharmacokinetic Model of the Rat Central Nervous System

1,†
,
2,‡
 and
1,*
Received: 7 November 2013 / Revised: 26 February 2014 / Accepted: 6 March 2014 / Published: 18 March 2014
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Abstract

Central nervous system (CNS) drug disposition is dictated by a drug’s physicochemical properties and its ability to permeate physiological barriers. The blood–brain barrier (BBB), blood-cerebrospinal fluid barrier and centrally located drug transporter proteins influence drug disposition within the central nervous system. Attainment of adequate brain-to-plasma and cerebrospinal fluid-to-plasma partitioning is important in determining the efficacy of centrally acting therapeutics. We have developed a physiologically-based pharmacokinetic model of the rat CNS which incorporates brain interstitial fluid (ISF), choroidal epithelial and total cerebrospinal fluid (CSF) compartments and accurately predicts CNS pharmacokinetics. The model yielded reasonable predictions of unbound brain-to-plasma partition ratio (Kpuu,brain) and CSF:plasma ratio (CSF:Plasmau) using a series of in vitro permeability and unbound fraction parameters. When using in vitro permeability data obtained from L-mdr1a cells to estimate rat in vivo permeability, the model successfully predicted, to within 4-fold, Kpuu,brain and CSF:Plasmau for 81.5% of compounds simulated. The model presented allows for simultaneous simulation and analysis of both brain biophase and CSF to accurately predict CNS pharmacokinetics from preclinical drug parameters routinely available during discovery and development pathways.
Keywords: physiologically-based pharmacokinetic model; blood–brain barrier; cerebrospinal fluid; unbound fraction; brain physiologically-based pharmacokinetic model; blood–brain barrier; cerebrospinal fluid; unbound fraction; brain
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Badhan, R.K.S.; Chenel, M.; Penny, J.I. Development of a Physiologically-Based Pharmacokinetic Model of the Rat Central Nervous System. Pharmaceutics 2014, 6, 97-136.

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