The transport of the anti‐HIV drug, 2′,3′‐didehydro‐3′‐deoxythymidine (D4T), across the blood‐brain and blood‐cerebrospinal fluid barriers

1. The brain is a site of infection, viral replication and sanctuary for HIV-1. The treatment of HIV-1 infection therefore requires that an effective agent be delivered to the brain. 2',3'-Didehydro-3'-deoxythymidine (D4T) is a nucleoside analogue which has been shown to have beneficial clinical effects in the treatment of HIV infection. However, although D4T has been detected in human CSF, the ability of this drug to cross both the blood-brain and blood-cerebrospinal fluid (CSF) barriers and gain entrance into the brain tissue is not known. 2. This study examined the CNS entry of D4T by means of the bilateral vascular brain perfusion technique in the anaesthetized guinea-pig. 3. The results indicated that [3H]-D4T had a limited ability to cross the blood-brain barrier (BBB), which was not significantly greater than D-[14C]-mannitol (a slowly penetrating marker molecule). Although D4T was found to cross the blood-CSF barrier, the presence of D4T in the CSF did not reflect levels of the drug in the brain tissue. 4. These results can be related to the measured low lipophilicity of D4T, the higher paracellular permeability characteristics of the choroid plexus (blood-CSF barrier) compared to the BBB, and the sink action nature of the CSF to the brain tissue. 5. In conclusion, these animal studies suggest that D4T may only penetrate the brain tissue to a limited extent and consideration should be given to these findings in the clinical situation.