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A Practical Perspective on the Evaluation of Small Molecule CNS Penetration in Drug Discovery

[ Vol. 13 , Issue. 2 ]


Liyue Huang*, Mary C. Wells and Zhiyang Zhao   Pages 78 - 94 ( 17 )


The separation of the brain from blood by the blood-brain barrier and the bloodcerebrospinal fluid (CSF) barrier poses unique challenges for the discovery and development of drugs targeting the central nervous system (CNS). This review will describe the role of transporters in CNS penetration and examine the relationship between unbound brain (Cu-brain) and unbound plasma (Cu-plasma) or CSF (CCSF) concentration. Published data demonstrate that the relationship between Cu-brain and Cu-plasma or CCSF can be affected by transporter status and passive permeability of a drug and CCSF may not be a reliable surrogate for CNS penetration. Indeed, CCSF usually over-estimates Cu-brain for efflux substrates and it provides no additional value over Cu-plasma as the surrogate of Cu-brain for highly permeable non-efflux substrates. A strategy described here for the evaluation of CNS penetration is to use in vitro permeability, P-glycoprotein (Pgp) and breast cancer resistance protein efflux assays and Cu-brain/Cu-plasma in preclinical species. Cu-plasma should be used as the surrogate of Cu-brain for highly permeable non-efflux substrates with no evidence of impaired distribution into the brain. When drug penetration into the brain is impaired, we recommend using (total brain concentration * unbound fraction in the brain) as Cu-brain in preclinical species or Cu-plasma/in vitro Pgp efflux ratio if Pgp is the major limiting mechanism for brain penetration.


Blood-brain barrier, blood-CSF barrier, BCRP, CNS penetration, CSF, P-glycoprotein, unbound brain concentration.


Epizyme Inc, 400 Technology Square, Cambridge, MA-02139, Vertex Pharmaceuticals, 50 Northern Ave, Boston, MA-02210, Alliance Pharma, Inc. 17 Lee Blvd. Malvern, PA-19355

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