Investigation of distribution, transport and uptake of anti-HIV drugs to the central nervous system.

The distribution of currently available anti-HIV drugs into the CNS is reviewed with a focus on transport mechanisms. Among these drugs, nucleoside analogs are most well studied for their CNS distribution. The average reported values of the CSF/plasma steady-state concentration or corresponding AUC ratios are 0.23 (AZT), 0.06 (ddI), 0.04 (ddC), 0.49 (d4T), and 0.08 (3TC). Active efflux transport out of the CNS appears to be a predominant mechanism limiting nucleoside access to the CNS, although poor penetration may contribute to some extent for some polar nucleosides. The nature of the efflux pump for these drugs is speculated to be MRP-like transporter(s) in blood-brain and blood-CSF barriers. For non-nucleoside and protease inhibitors, much research remains to be done on the extent, time course, and mechanisms of their CNS distribution. The CNS penetration of some protease inhibitors is restricted by P-glycoprotein. A better understanding of transport mechanisms of anti-HIV drugs in the CNS is essential to develop approaches to enhance CNS delivery of available drugs and to identify new drugs less subject to active efflux transporter(s) in the CNS.