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Review
. 2021 Aug;41(8):1797-1820.
doi: 10.1177/0271678X20985946. Epub 2021 Jan 14.

Understanding the brain uptake and permeability of small molecules through the BBB: A technical overview

Ekram Ahmed Chowdhury  1 , Behnam Noorani  1 , Faleh Alqahtani  2 , Aditya Bhalerao  3 , Snehal Raut  1 , Farzane Sivandzade  3 , Luca Cucullo  3
Affiliations
Review

Understanding the brain uptake and permeability of small molecules through the BBB: A technical overview

Ekram Ahmed Chowdhury et al. J Cereb Blood Flow Metab. 2021 Aug.

Abstract

The brain is the most important organ in our body requiring its unique microenvironment. By the virtue of its function, the blood-brain barrier poses a significant hurdle in drug delivery for the treatment of neurological diseases. There are also different theories regarding how molecules are typically effluxed from the brain. In this review, we comprehensively discuss how the different pharmacokinetic techniques used for measuring brain uptake/permeability of small molecules have evolved with time. We also discuss the advantages and disadvantages associated with these different techniques as well as the importance to utilize the right method to properly assess CNS exposure to drug molecules. Even though very strong advances have been made we still have a long way to go to ensure a reduction in failures in central nervous system drug development programs.

Keywords: Blood-brain barrier; brain vascular volume correction; permeability; pharmacokinetics; small molecules.

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Conflict of interest statement

Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
A schematic illustration of the different types of transport feasible across the BBB. The different modes of transport feasible across the BBB are as follows: 1) Simple diffusion, 2) Facilitated diffusion, 3) Absorptive Transcytosis, 4) Receptor-Mediated Transcytosis and 5) Active Transport (Primary and secondary). Typically, BBB permeable molecules can cross-diffusion (water-soluble molecules can diffusion paracellularly through the tight junction proteins, while lipophilic molecules take the transcellular route). There are numerous transporters present on the BBB that allow facilitated diffusion of different nutrients such as glucose, amino acids, nucleosides, and other molecules (i.e. Glut1, LAT1, etc.). Other than this, small molecules can also be transported by active transport, a process that uses energy in the form of ATP to transport molecules against a concentration gradient. Active transport mechanisms can be divided into primary active transport and secondary active transport. Efflux transport by different ABC transporters such as P-gp is a good example of primary active transport. Secondary active transport typically couples the movement of an ion-molecule with another molecule that is transported against its concentration gradient. Macromolecules are typically transported via absorptive transcytosis (i.e. albumin) or receptor-mediated transcytosis (i.e. insulin and transferrin, etc.).
Figure 2.
Figure 2.
An illustration of the distribution of small molecule drugs within the CNS after entry into the brain through the BBB. Typically, molecules entering the brain through different transport mechanisms are subjected to diffusive transport in the brain parenchyma. However, this transport process is rather slow to allow rapid distribution in CNS since the brain extracellular space is very narrow and tortuous with a space of just ∼50 nm between cells. Molecules in the perivascular spaces are subject to convective transport and can be transported much faster via this mechanism. This phenomenon most probably contributes to the ease of transport of molecules from Brain Parenchyma to the CSF in subarachnoid space, the Cisterna Magna as well as the ventricles.
Figure 3.
Figure 3.
An illustration of the single time points analysis technique.
Figure 4.
Figure 4.
An illustration of the Patlak plot.
Figure 5.
Figure 5.
An illustration of the brain perfusion technique (adapted from Takasato et al.).
Figure 6.
Figure 6.
Illustration of a typical microdialysis apparatus for sampling small-molecule drugs from the brain parenchyma.
Figure 7.
Figure 7.
A schematic illustration of a translational brain PBPK model (adopted from de Lange).
See this image and copyright information in PMC

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