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 moiety via an ester bond were synthesized to improve the transport of AZT into the central nervous system (CNS). In in vitro degradation studies with rat and human plasma, it was demonstrated that the prodrugs were degraded enzymatically and converted quantitatively to their parent 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 prodrugs were administered intravenously to rat, the prodrugs in brain tissue were detected at 7-18 times higher concentrations than AZT in spite of the negligible amount of the prodrug in the cerebrospinal fluid. These results indicate that the introduction to AZT of the 1-adamantane moiety results in the enhancement of the BBB penetration. This pharmaceutical approach would be beneficial for the efficient treatment of the CNS infection by human immunodeficiency virus.