BRAIN TARGETING OF ANTI-HIV NUCLEOSIDES - IN-VITRO AND IN-VIVO EVALUATION OF 6-CHLORO-2',3'-DIDEOXYPURINE, A LIPOPHILIC PRODRUG OF 2',3'-DIDEOXYINOSINE

Lipophilic 6-halo-2',3'-dideoxypurine nucleosides may be useful prodrugs for the targeting of 2',3'-dideoxyinosine (ddl) to the central nervous system. The purpose of this study was to evaluate the potential effectiveness of 6-chloro-2',3'-dideoxypurine (6-Cl-ddP) for the targeting of ddl to the brain. In vitro studies indicated that the adenosine deaminase-mediated biotransformation of 6-Cl-ddP to ddl was more rapid in mouse brain homogenate than in mouse serum. The brain distribution of 6-Cl-ddP and ddl was assessed in vivo in mice following intravenous and oral administration of the prodrug or parent drug. Brain concentrations of ddl were similar after intravenous administration of 6-Cl-ddP or ddl. However, after oral administration of the 6-Cl-ddP prodrug, significantly greater concentrations of ddl were seen in the brain compared to those found after oral administration of ddl. The brain:serum AUC ratio (expressed as a percentage) of ddl after intravenous administration of 50 mg kg(-1) of the active nucleoside was 3%. Following oral administration of 250 mg kg(-1) ddl, low concentrations of ddl were detected in the brain. Brain:serum AUC ratios following intravenous and oral administration of the prodrug 6-Cl-ddP were 19-25%. Thus, brain:serum AUC ratios were 6- to 8-fold higher after prodrug administration than those obtained after administration of the parent nucleoside. Oral administration of 6-Cl-ddP yielded concentrations of ddl in the brain similar to those obtained following intravenous administration. The results of this study provide further evidence that 8-Cl-ddP may be a useful prodrug for delivering ddl to the central nervous system, particularly after oral administration.