I've updated the brain penetration page to include data from a recent publication, Small Molecule Kinase Inhibitors for the Treatment of Brain Cancer DOI which discusses the issues with targeting brain and central nervous system cancers.

The brain is protected from xenobiotic agents by the blood-brain barrier (BBB) 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. 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. It is also one of the transporters found to be up-regulated in some drug-resistant tumors and is considered to be one of the major causes of treatment failure.

An interesting publication by Kim and Bynoe in J Clin Invest DOI show that activation of the A2A adenosine receptor (AR) with an FDA-approved A2A AR agonist (Lexiscan) rapidly and potently decreased P-gp expression and function in a time-dependent and reversible manner.

They demonstrate that down modulation of P-gp expression and function coincided with chemotherapeutic drug accumulation in brains of WT mice and in primary mouse and human brain endothelial cells, which serve as in vitro BBB models.

I’ve updated the Drug Discovery Resources, in particular I’ve updated the section on Brain Penetration to include more on predictive models.

I’ve also updated the page on Grant Funding Research.