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Expert opinion on drug delivery
2024 Jan-Jun;21 (1): 71-89.

Blood-brain barrier transporters: a translational consideration for CNS delivery of neurotherapeutics.

Patrick T Ronaldson, Thomas P Davis
Author Information
  1. Patrick T Ronaldson: Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA.
  2. Thomas P Davis: Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA.
PMID: 38217410 DOI: 10.1080/17425247.2024.2306138

Abstract

INTRODUCTION: Successful neuropharmacology requires optimization of CNS drug delivery and, by extension, free drug concentrations at brain molecular targets. Detailed assessment of blood-brain barrier (BBB) physiological characteristics is necessary to achieve this goal. The 'next frontier' in CNS drug delivery is targeting BBB uptake transporters, an approach that requires evaluation of brain endothelial cell transport processes so that effective drug accumulation and improved therapeutic efficacy can occur.
AREAS COVERED: BBB permeability of drugs is governed by tight junction protein complexes (i.e., physical barrier) and transporters/enzymes (i.e., biochemical barrier). For most therapeutics, a component of blood-to-brain transport involves passive transcellular diffusion. Small molecule drugs that do not possess acceptable physicochemical characteristics for passive permeability may utilize putative membrane transporters for CNS uptake. While both uptake and efflux transport mechanisms are expressed at the brain microvascular endothelium, uptake transporters can be targeted for optimization of brain drug delivery and improved treatment of neurological disease states.
EXPERT OPINION: Uptake transporters represent a unique opportunity to optimize brain drug delivery by leveraging the endogenous biology of the BBB. A rigorous understanding of these transporters is required to improve translation from the bench to clinical trials and stimulate the development of new treatment paradigms for neurological diseases.

Keywords

ABC transporters SLC transporters blood-brain barrier drug delivery endothelial cell neuropharmacology passive diffusion

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Grants

  1. R01 DA051812/NIDA NIH HHS
  2. R01 NS084941/NINDS NIH HHS

MeSH Term

Blood-Brain Barrier
Brain
Membrane Transport Proteins
Biological Transport
Pharmaceutical Preparations
Central Nervous System Agents

Chemicals

Membrane Transport Proteins
Pharmaceutical Preparations
Central Nervous System Agents
Journal Article Review

Word Cloud

Created with Highcharts 10.0.0drugtransportersdeliverybrainbarrierCNSBBBuptaketransportpassiveneuropharmacologyrequiresoptimizationblood-braincharacteristicsendothelialcellimprovedcanpermeabilitydrugsiediffusiontreatmentneurologicalINTRODUCTION:SuccessfulextensionfreeconcentrationsmoleculartargetsDetailedassessmentphysiologicalnecessaryachievegoal'nextfrontier'targetingapproachevaluationprocesseseffectiveaccumulationtherapeuticefficacyoccurAREASCOVERED:governedtightjunctionproteincomplexesphysicaltransporters/enzymesbiochemicaltherapeuticscomponentblood-to-braininvolvestranscellularSmallmoleculepossessacceptablephysicochemicalmayutilizeputativemembraneeffluxmechanismsexpressedmicrovascularendotheliumtargeteddiseasestatesEXPERTOPINION:UptakerepresentuniqueopportunityoptimizeleveragingendogenousbiologyrigorousunderstandingrequiredimprovetranslationbenchclinicaltrialsstimulatedevelopmentnewparadigmsdiseasesBlood-braintransporters:translationalconsiderationneurotherapeuticsABCSLC

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