ADAMANTANE AS A BRAIN-DIRECTED DRUG CARRIER FOR POORLY ABSORBED DRUG .2. AZT DERIVATIVES CONJUGATED WITH THE 1-ADAMANTANE MOIETY

Five AZT (azidothymidine) prodrugs conjugated with the 1-adamantane mo iety via an ester bond were synthesized to improve the transport of AZ T into the central nervous system (CNS). In in vitro degradation studi es with rat and human plasma, it was demonstrated that the prodrugs we re degradated enzymatically and converted quantitatively to their pare nt drug, AZT. As assessed by octanol-buffer partitioning, the prodrugs were much more lipophilic than AZT and were expected to penetrate the blood-brain barrier (BBB) readily. In in vivo studies, in which the p rodrugs were administered intravenously to rat, the prodrugs in brain tissue were detected at 7-18 times higher concentrations than AZT in s pite of the negligible amount of the prodrug in the cerebrospinal flui d. These results indicate that the introduction to AZT of the 1-adaman tane moiety results in the enhancement of the BBB penetration. This ph armaceutical approach would be beneficial for the efficient treatment of the CNS infection by human immunodeficiency virus.