Recent Advances in the In Vitro and In Vivo Methods to Assess Impact of P-gp and BCRP CNS Drug Disposition

doi: 10.1002/bdd.2345.

Online ahead of print.


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Sagnik Chatterjee et al.

Biopharm Drug Dispos.



One challenge in CNS drug discovery has been ensuring blood brain barrier (BBB) penetration of compounds at an efficacious concentration that provides suitable safety margins for clinical investigation. Research providing for accurate prediction of brain penetration of compounds during preclinical discovery is important to a CNS program. In the BBB, P-gp (ABCB1) and BCRP (ABCG2) transporters have been demonstrated to play a major role in active efflux of endogenous compounds and xenobiotics out of the brain microvessel cells and back to systemic circulation. In the past 10 years, there has been significant technological improvement in the sensitivity of quantitative proteomics methods, in vivo imaging, in vitro methods of organoid and microphysiological systems (MPS), as well as in silico quantitative physiological based pharmacokinetic (PBPK) and systems pharmacology models. Scientists continually leverage these advancements to interrogate the distribution of compounds in the CNS which may also show signals of substrate specificity of P-gp and/or BCRP. These methods have shown promise towards predicting and quantifying the unbound concentration(s) within the brain relevant for efficacy or safety. In this review, the authors have summarized the in vivo, in vitro and proteomics advancements towards understanding the contribution of P-gp and/or BCRP in restricting entry of compounds in CNS of either healthy or special population. Special emphasis has been provided on recent investigations on the application of proteomics-informed approach to predict steady-state drug concentrations in the brain. Moreover, future perspectives regarding role of these transporters in newer modalities are described. This article is protected by copyright. All rights reserved.


BCRP; CNS drug disposition; P-gp; and IVIVE; proteomics.

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