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Report of Research Into Transport of Zavesca Into the Brain

In the July 2009 edition of Gauchers News, we reported on a grant to Dr David Begley from Kings College, London to support work being undertaken to study how Zavesca gets into the brain.  Dr Begley reports on the outcome of this study and offers some observations:

The so called blood-brain barrier is created by the smallest blood vessels in the brain - the capillaries - and regulates very closely what gets into and out of the brain. This barrier makes sure that the environment of the brain is kept very constant so that the brain can work at optimum efficiency. It also protects the brain from harmful substances that might be circulating in the blood. Unfortunately this blood-brain barrier also severely limits the access of many drugs to the brain that we might want to use to treat brain disease. Until this study was done we had no detailed knowledge of how Zavesca might cross the blood-brain barrier. Zavesca is clearly very useful in treating peripheral storage in Gaucher disease but we didn\'t really know whether it easily reached the brain.

Studies were carried out in mice and in human brain endothelial cells, the cells that form the blood-brain barrier. We had Zavesca specially made with a radioactive label incorporated into the molecule by GE Healthcare. The results clearly show that Zavesca does enter the brain but at a relatively slow rate. This rate is some two and a half times faster than sugar sucrose (the sugar we cook with) but compared to a drug like the alcohol in beer it is some one thousand times slower.

Zavesca is itself a sugar, first extracted from mulberry leaves by Chinese herbalists, but it\'s a specialised plant sugar which cannot be metabolised by mammals or humans. Our studies indicate that Zavesca does not use a sugar transporter to get into cells and movement across the cell membrane is largely by simple diffusion (dispersion). However the movement of Zavesca into cells is partly dependent on the sodium outside of the cell and thus it might have a very low affinity for the sodium-dependent glucose transporter (SGLT); a transporter which both carries the sugar glucose across cell membranes and is the sugar which is used to power our cells.

SGLT is mainly found in the intestine and the kidney but is present in all cells to a limited extent. We also discovered that the movement of Zavesca across the cell membrane is dependent on the acidity of the solution in which the cells are placed. At normal body acidity the movement of Zavesca across the cell membrane is fastest. Once inside the cells the environment is more acid and the Zavesca does not come out as quickly as it goes in. We were able to confirm with the human endothelial cells that the Zavesca enters the cells faster than it leaves until the concentrations inside and outside become equal. Inside the lysosome it is very acid and once inside this the Zavesca would be almost trapped. This observation suggests that cells exposed to Zavesca for long periods might eventually build up high concentrations of the drug. We also showed that Zavesca is not subject to any active transport out of the cell.

Given the chemical properties of Zavesca we would not have predicted that it would enter cells so slowly, so it remains an enigmatic drug.  Other sugars related to Zavesca such as miglitol and isofagomine may have different properties in this respect and may be useful in the treatment of neuronopathic Gaucher disease, and should therefore be investigated.

Dr Begley has been invited to visit Actelion in November to deliver a full report on this research and it is hoped that this may lead to further support for this work.