Development of a physiologically-based pharmacokinetic model of the rat central nervous system

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.

Publication DOI: https://doi.org/10.3390/pharmaceutics6010097
Divisions: College of Health & Life Sciences > Aston Pharmacy School
College of Health & Life Sciences
College of Health & Life Sciences > Chronic and Communicable Conditions
Additional Information: 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 [Attribution 3.0 Unported (CC BY 3.0)].
Uncontrolled Keywords: blood-brain barrier,brain,cerebrospinal fluid,physiologically-based pharmacokinetic model,unbound fraction,Pharmaceutical Science
Publication ISSN: 1999-4923
Last Modified: 17 Jan 2024 08:05
Date Deposited: 11 May 2015 11:00
Full Text Link: http://www.mdpi ... 999-4923/6/1/97
Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2014-03-18
Authors: Badhan, Raj K. Singh (ORCID Profile 0000-0002-0904-9324)
Chenel, Marylore
Penny, Jeffrey I.

Download

[img]

Version: Published Version

License: Creative Commons Attribution


Export / Share Citation


Statistics

Additional statistics for this record