Prodrugs for improved CNS delivery

The blood-brain barrier is both a transport and an enzymatic barrier. The design of prodrugs for improved CNS delivery must necessarily address that barrier component which is playing the most important role in impeding the CNS uptake for a given parent compound. Because the capillaries within the blood-brain barrier are joined by tight junctions, the transport barrier is comprised of the lipid bilayer membranes of the capillary endothelial cells. Increasing parent drug lipophilicity is usually one element, therefore, in prodrug design. However, increased lipophilicity without the appropriate rate and selectivity of prodrug bioconversion in the brain will result in failure. To achieve the optimal bioconversion rates and selectivities, consideration of the enzymes present in brain tissue and in the BBB capillaries is essential. A number of enzymes appear to be localized in the cerebral microvasculature. A focus of this review is the prodrug approaches based on the utilization of these enzymes for bioconversion and the value of these approaches in achieving selectivity in delivery.