Impact of transporters and enzymes from blood–cerebrospinal fluid barrier and brain parenchyma on CNS drug uptake

ABSTRACT

Introduction: In parallel with the blood–brain barrier (BBB), transporters and enzymes on the blood–cerebrospinal fluid barrier (BCSFB) serve as the first barrier for drug brain uptake. In addition, their expressions on brain parenchyma are considered as the secondary barrier for central nervous system (CNS) drug delivery. Currently, a lack of information on transporters and enzymes expressed on both BCSFB and brain parenchyma is the major cause of failure in CNS drug development.

Areas covered: Transporters and enzymes expressed on BCSFB and brain parenchyma and their impact on drug brain uptake were highlighted and compared with that on BBB.

Expert opinion: Based on the nature of transporters expressed on BCSFB and the brain parenchyma, the design of CNS therapeutics with chemical structures similar to the substrates of nutrients and hormones transporters could facilitate their CSF and brain parenchyma uptake . Moreover, drugs in systemic circulation could undergo further metabolism at BCSFB and brain parenchyma leading to failure in CNS drug delivery. Impact of the altered expressions and functions of transporters and enzymes on BCSFB and brain parenchyma in different species or disease conditions on CNS drug brain uptake shall be further evaluated using relevant in vitro cell models and pharmacokinetics modeling.

KEYWORDS:

• BCSFB
• brain parenchyma
• transporter
• enzyme
• CNS drug delivery

Article highlights

• In parallel with those on BBB, transporters and enzymes expressed on BCSFB could serve as the first barrier for drug uptake into the brain due to the relatively large surface area of BCSFB in the human brain.

• Although transporters expressed on BCSFB overlapped with that on BBB, a number of them could demonstrate different transport directions.

• Majority of Phase I and Phase II metabolic enzymes on BCSFB or brain parenchyma were characterized in mice or rats with limited information available from the human brain.

• Transporters and enzymes expressed on brain parenchyma served as the secondary barrier for its drug uptake. The fact that the majority of transporters expressed on brain parenchyma were efflux transporters suggesting that screening out substrates of such transporters is essential in the early stage of drug development. On the other hand, a potential approach to increase drug uptake into brain parenchyma is to design therapeutics mimicking the substrate for influx transporters including glucose, choline, amino acid, and neurotransmitter transporters.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.