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 fo r HIV-1. The treatment of HIV-1 infection therefore requires that an e ffective agent be delivered to the brain. 2',3'-Didehydro-3'-deoxythym idine (D4T) is a nucleoside analogue which has been shown to have bene ficial clinical effects in the treatment of HIV infection. However, al though D4T has been detected in human CSF, the ability of this drug to cross both the blood-brain and blood-cerebrospinal fluid (CSF) barrie rs and gain entrance into the brain tissue is not known.2 This study e xamined the CNS entry of D4T by means of the bilateral Vascular brain perfusion technique in the anaesthetized guinea-pig. 3 The results ind icated that [H-3]-D4T had a limited ability to cross the blood-brain b arrier (BBB), which was not significantly greater than D-[C-14]-mannit ol (a slowly penetrating marker molecule). Although D4T was found to c ross the blood-CSF barrier, the presence of D4T in the CSF did not ref lect levels of the drug in the brain tissue. 4 These results can be re lated to the measured low lipophilicity of D4T, the higher paracellula r permeability characteristics of the choroid plexus (blood-CSF barrie r) compared to the BBB, and the sink action nature of the CSF to the b rain tissue. 5 In conclusion, these animal studies suggest that D4T ma y only penetrate the brain tissue to a limited extent and consideratio n should be given to these findings in the clinical situation.