The role of the efflux transporter, P‐glycoprotein, at the blood–brain barrier in drug discovery

Abstract

The blood–brain barrier (BBB) expresses a high abundance of transporters, particularly P‐glycoprotein (P‐gp), that regulate endogenous and exogenous molecule uptake and removal of waste. This review discusses key drug metabolism and pharmacokinetic considerations for the efflux transporter P‐gp at the BBB in drug discovery and development. We highlight the differences in P‐gp expression and protein levels across species but the limited observations of species‐specific substrates. Given the impact of age and disease on BBB biology, we summarise the modulation of P‐gp for several neurological disorders and ageing and exemplify several disease‐specific hurdles or opportunities for drug exposure in the brain. Furthermore, the review includes observations of CNS‐related drug‐drug interactions due to the inhibition or induction of P‐gp at the BBB in animal studies and humans and the need for continued evaluation especially for compounds with a narrow therapeutic window. This review focusses primarily on small molecules but also considers the impact of new chemical entities, particularly beyond Ro5 molecules and their potential to be recognised as P‐gp substrates as well as advanced drug delivery systems which offer an alternative approach to achieve and sustain central nervous system exposure.

Circadian Rhythms of the Blood-Brain Barrier and Drug Delivery

“…The BBB also has a higher density of certain transporter proteins and enzymes compared with other blood vessels. 9 These proteins actively regulate the transport of substances across the barrier, allowing the selective passage of molecules essential for brain function while limiting the entry of potentially harmful substances. The BBB's primary function is to maintain the delicate homeostasis of the brain microenvironment by forming a continuous seal between cells that restricts the passage of nearly all blood-borne substances through the intercellular (between-cells) space, effectively preventing toxins and pathogens from reaching the brain.…”

“…22 These transporters are highly enriched and exhibit apical/luminal localization in across species ( Drosophila , mice, rat, and humans) but the expression level and distribution are species dependent. 9,21,22 Interestingly, the expression of P-gp in BBB of rodents is 8× higher in mice and 2.6× higher in rats compared with that of humans. P-pg spatial expression in microvessels throughout different brain regions may also vary by organism.…”

“…The BBB also has a higher density of certain transporter proteins and enzymes compared with other blood vessels. 9 These proteins actively regulate the transport of substances across the barrier, allowing the selective passage of molecules essential for brain function while limiting the entry of potentially harmful substances.…”

Targeted protein degradation in CNS disorders: a promising route to novel therapeutics?

“…A CNS penetrant PROTAC must balance sufficient polarity to provide specific target engagement and solubility while crossing the BBB ( Doak et al, 2014 ). Additionally, increased efflux is common in bRo5 ( Doak et al, 2014 ; Matsson et al, 2016 ; Cantrill et al, 2020 ; Cox et al, 2023 ) and PROTAC development space ( Klein et al, 2021 ). Beyond CNS considerations, the combination of differentiated property space (in particular lipophilicity) and pharmacology results in additional considerations around absorption, distribution, metabolism, and excretion (ADME) testing ( Cantrill et al, 2020 ; Pike et al, 2020 ; Apprato et al, 2023 ; Hornberger and Araujo, 2023 ; Volak et al, 2023 ).…”

Computational Discovery of Potent Imidazole Derivatives as Inhibitors of SARS-CoV-2 Main Protease: An Integrated Approach Combining Molecular Dynamics and Binding Affinity Analysis

“…Consequently, compounds that are Pgp substrates may exhibit lower oral bioavailability. Moreover, Pgp is expressed in the blood-brain barrier and other tissues(Cox et al, 2023). Its activity can limit the penetration of Pgp substrate drugs into the brain and other target tissues,…”