Brain Penetration

The brain is protected from xenobiotic agents by the blood-brain barrier (BBB). The BBB is a network of capilliaries lined by endothetial cells characterised by lack of fenestrations and very tight junctions between the cells. This restricts paracelleular diffusion of molecules, in addition there are a number of active transport mechanisms for transporting molecules into and more abundantly out of the brain. There are a number of energy dependent transporter proteins that are capable of binding to a wide variety of substrates and pumping them back into the plasma, perhaps the best known of which is multidrug resistance protein (MDR). In contrast there are a number of specific carriers for essential molecules (amino acids, glucose, nucleosides).

In vitro models of the BBB.

Several artificial membranes have been used to model BBB penetration, however most lack the correct morphology and expression levels of the transporter proteins, in particular the Caco-2 cell line used to predict
intestinal absorption very poorly predicts brain penetration. The MDCK cell line transfected with the multi-drug resistance gene (MDR-MDCK) has been used to model BBB penetration and has been shown to correlate with in vivo studies (Int. J. Pharm. 2005, 288, 349).
Whilst these models do give an estimate of the intrinsic ability of a molecule to cross the membrane you need to bear in mind that
binding to plasma proteins can also limit brain penetration in vivo. In addition the intrinsic pharmacokinetics of the compound may overcome any liabilities identified in vitro.

In vivo studies

Probably the most often used measure of brain penetration is the partition between blood plasma and whole brain (log BB), whilst relatively straight forward to measure
this can be highly misleading. Many highly lipophilic molecules partion extesively into the brain tissue but are not available to act on the target protein. It is much better to either measure the free unbound drug concentrations or use a receptor occupancy or pharmacological assay if possible.
There has been increased use of imaging techniques to more accurately measure both BBB penetration and target protein occupancy, whilst enormously valuable the development of a PET tracer can require as much effort as a drug discovery program! Microdialysis and ex-vivo binding assays provide very high quality information but do require dedicated expertise.

Molecular Properties Effecting BBB penetration

As might be expect lipophilicity has a major effect on BBB penetration, and early studies highlighted the parabolic relationship between LogP and CNS activity
in vivo in rodents. A recent study (Med. Chem.: Cent. Nerv. Syst. Agents 2002, 2, 229-240 ) looking at BBB penetration of CNS active drugs provides useful guidelines.

Suggested Physicochemical Property Ranges for Increasing the Potential for BBB Penetration.

Property top 25 CNS drugs mean suggested limits % of top 25 CNS drugs in suggested range preferred range % of top 25 CNS drugs in preferred range
PSA (A2) 47 <90 96 <70 76
HBD 0.8 <3 100 0-1 92
cLogP 2.8 2-5 68 2-4 52
clogD (pH 7.4) 2.1 2-5 61 2-4 61
MW 293 <500 100 <450 100

Transporter mediated efflux of drugs is major issue in drug discovery. The best understood of the transporters is ABCB1 also known as P-gp, MDR1 (mdr1 in rodents) this transporter is present in the blood-brain barrier, in the gut, on hepatocytes, and the kidney.

Last Updated 3 Feb 2010
See Also
See Also
Back to ADME Properties
Back to
Drug Discovery Resources