THE PASSAGE OF AZIDODEOXYTHYMIDINE INTO AND WITHIN THE CENTRAL-NERVOUS-SYSTEM - DOES IT FOLLOW THE PARENT COMPOUND, THYMIDINE

The transport of azidodeoxythymidine (AZT) into and within the central nervous system (CNS) has special clinical significance due to the abi lity of AZT to alleviate certain neurological symptoms associated with the acquired immunodeficiency syndrome (AIDS). AZT was thought to be similar to its parent compound, thymidine, in that it entered the CNS via the choroid plexuses (blood-CSF barrier) and could not cross the b lood-brain barrier (BBB). However, a saturable transport system for th ymidine at the BBB has recently been identified. The aim of this study was to test the hypothesis that AZT follows its physiological counter part in its mode of entry into and movement within the CNS. Initial ex periments using the in situ brain perfusion technique indicated that t he blood-to-CNS transfer constants for [H-3]AZT (blood-to-cerebrum; 0. 95 +/- 0.12 mu l/min/g) were significantly lower than those determined for [H-3]thymidine. Also, [H-3]AZT entered the CNS purely by a diffus ive process. The movement of [H-3]AZT within the CNS was further inves tigated by a ventriculocisternal perfusion technique and indicated tha t the majority of intraventricularly perfused [H-3]AZT remained within the ventricles (79.9%), with little escaping to blood (14.1 +/- 3.1%) or brain (6.0 +/- 1.3%). Overall, these results suggest that the chor oid plexus/CSF pathway was unlikely to be solely responsible for the l evels of [H-3]AZT observed in brain and that the BBB plays a significa nt role in the brain entry of this analog. However, in contrast to thy midine, AZT enters the CNS purely by a diffusional process.