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Updated: May 17, 2026

A Human Blood-Brain Interface Model to Study Barrier Crossings by Pathogens or Medicines and Their Interactions with the Brain
Published on: April 9, 2019
Demystifying brain penetration in central nervous system drug discovery. Miniperspective
1Pfizer Inc., Groton, Connecticut 06340, USA. Li.Di@Pfizer.com
Abstract:
This Perspective provides important concepts about the blood-brain barrier (BBB) in drug discovery and how they should be applied effectively in designing successful CNS drugs. Key parameters for brain penetration are discussed, including unbound brain concentration, unbound brain-to-plasma ratio, BBB permeability, fraction unbound in brain and plasma, and transporters. Results from a retrospective analysis of 32 Pfizer CNS clinical drug candidates are described. Frequently encountered misconceptions about brain penetration in drug discovery programs are clarified. Strategies and guidance are provided to enhance or minimize brain exposure for CNS or peripheral targets, respectively. Recommendations for screening methodologies and a cascade in assessing brain penetration potential are presented.
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