The candidate-killer BBBs

One of the biggest challenges in developing treatments for CNS disorders is finding efficacious compounds that are capable of crossing the blood-brain barrier (BBB). Several in vitro assays have been developed to identify the apparent permeability (Papp) of compounds, but these results don’t always match the actual permeability (P) found in vivo.

Randall C Willis
HARLOW, U.K.—One of the biggest challenges in developing treatments for CNS disorders is finding efficacious compounds that are capable of crossing the blood-brain barrier (BBB). Several in vitro assays have been developed to identify the apparent permeability (Papp) of compounds, but these results don't always match the actual permeability (P) found in vivo. Several researchers examined this question more closely, describing their efforts in JPET.
 
Researchers at GSK, Kings College London, Absorption Systems, and UCB Celltech tested 50 marketed CNS drugs representing a cross-section of physicochemical properties and chemical space, looking for patterns of compound behavior in cell permeability (in vitro) and rat brain perfusion (in vivo) studies. They found that the lipophilicity of a drug had a significant impact on how well Papp correlated with P, such that for compounds with clogP < 3, there is a linear correlation between the two, but this correlation is lost for compounds with higher clogP values.
 
They also noted that because the CNS compartment is comprised not only of the BBB but also the brain parenchyma, in vivo drug uptake may involve many more factors than can be modeled with in vitro assays. The researchers speculate that P may be influenced by the intrinsic permeability of the BBB as well as the affinity of the drug for brain tissue, where the latter acts as a sink to swing drug distribution toward uptake.
 
And finally, they suggest that discrepancies between Papp and P may also be explained by active uptake mechanisms that exist in vivo but not in vitro. For example, they highlight gabapentin, which is recognized by an amino acid transporter in the BBB. The compound exhibits poor passive permeability despite having a significant P value.

Randall C Willis

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