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Advanced Neurology Brain bioavailability of targeted protein degraders

B-CSF barriers are interconnected and nearly identical. candidates, the concentration of TPD in the CSF should
However, it is important to recognize that the B-CSF not be considered a direct indicator of CNS bioavailability
barrier is more permeable than the BBB, and the molecular due to the differing permeability characteristics of the
weight of circulating molecules (inversely proportional to BBB and the B-CSF barrier. In addition, the unbound
their ability to cross) remains a key determinant of their brain-to-plasma partition coefficient (K p,uu,brain ) should be
entry into the CSF. Thus, the distribution of a compound estimated. However, at the early discovery stage, CSF
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in the CSF primarily reflects transport through the CP at concentrations can be considered a surrogate for K p,uu,brain .
the B-CSF barrier, rather than serving as a direct indicator
of BBB penetration ability. 7. The arachnoid barrier
When a drug is injected into the CSF, it first permeates The avascular arachnoid epithelium, located underneath
into the bloodstream before crossing the BBB to re-enter the dura mater, forms the arachnoid barrier. The dura
brain tissue, subjected to molecules’ physiochemical mater, part of the meninges, lies just beneath the bone and
properties. This process is illustrated in Figure 3. envelops the CNS, thus forming a seal between the CNS’s
ECF and the rest of the body. The arachnoid barrier plays
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On the contrary, the drug rapidly equilibrates
throughout the entire volume of the brain after crossing an insignificant role in the exchange of xenobiotics between
the BBB from the blood. This phenomenon suggests that the blood and brain, primarily due to its avascular nature
drugs injected directly into the CSF may exhibit transient and its relatively small surface area compared to the BBB or
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pharmacological benefits, but only after the drug is B-CSF barrier. Furthermore, the efflux transporter P-gp is
transported from the CSF to the blood and then re-enters expressed on the apical membrane toward the dura mater,
the brain through the BBB, enabling a full pharmacological and BCRP is expressed on both the apical membrane
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response. This notion is further supported by a study on toward the dura mater and the basal membrane toward
barbiturate intracerebroventricular administration in dogs. the CSF. Therefore, the pharmacological relevance of the
Regardless of whether the barbiturate was administered by arachnoid barrier in drug uptake is relatively insignificant
intravenously (IV) or through the intracerebroventricular and has not been discussed in detail in this review.
route, the amount required to maintain the anesthesia for To facilitate blood-parenchyma exchange, endothelial
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the necessary duration was the same: 0.2 mg/kg/min. cells express receptors and transporters. The active efflux
Hence, drug penetration into the CSF, when estimated for pumps out brain materials by ATP binding cassette
any molecule, does not necessarily correlate with the drug’s transporters for example P-glycoprotein and Breast Cancer
penetration through the BBB at the endothelium level of the Resistance Protein. The influx and efflux transporters
brain capillaries, nor with CNS bioavailability in general. and their respective substrates and inhibitors have been
CSF is sampled for compounds whose transporters are not illustrated in Figure 4.
yet known or identified. TPD concentrations quantified in
the CSF are a good predictor of the unbound concentration 8. Influx transporters
in the brain, unless specific transport mechanisms exist Various SLC transporters are expressed by brain capillary
between the brain and CSF. When selecting clinical endothelial cells to facilitate brain absorption. SLC7A5/L-
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type amino acid transporter 1 (LAT1) is a transmembrane
heterodimeric protein predominantly expressed in
neurons, astrocytes, and microglia, and specifically at
both the luminal and abluminal sides of the BBB. LAT1
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and SLCO2B1/OATP2B1 are reported to have the highest
expression levels in microvessels. Furthermore, brain
microvessels express significant amounts of SLC2A1/
glucose transporter 1 (GLUT1), as well as the glutamate
transporters SLC1A2/excitatory amino acid transporter
(EAAT) 2 and SLC1A3/EAAT1.

Antioxidant ascorbic acid (AA) protects lipid
membranes and proteins from oxidative damage.
Two transport proteins in the brain can transport
L-AA: GLUT1 and the sodium-dependent vitamin C
Figure 3. Drug kinetics from blood-cereberospinal fluid to blood–brain transporter 2. GLUT1 transports the oxidized form of AA,
barrier. Image created by the authors. that is, dehydroascorbic acid, which is then reduced to

Volume 4 Issue 2 (2025) 58 doi: 10.36922/an.5140