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 (ddI) 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 ddI to the brain. In vitro studies indicated that the adenosine deaminase-mediated biotransformation of 6-Cl-ddP to ddI was more rapid in mouse brain homogenate than in mouse serum. The brain distribution of 6-Cl-ddP and ddI was assessed in vivo in mice following intravenous and oral administration of the prodrug or parent drug. Brain concentrations of ddI were similar after intravenous administration of 6-Cl-ddP or ddI. However, after oral administration of the 6-Cl-ddP prodrug, significantly greater concentrations of ddI were seon in the brain compared to those found after oral administration of ddI. The brain:serum AUC ratio (expressed as a percentage) of ddI after intravenous administration of 50 mg kg^-1 of the active nucleoside was 3%. Following oral administration of 250 mg kg^-1 ddI, low concentrations of ddI 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 ddI in the brain similar to those obtained following intravenous administration. The results of this study provide further evidence that 6-Cl-ddP may be a useful prodrug for delivering ddI to the central nervous system, particularly after oral administration.