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

• Published in: Antiviral chemistry & chemotherapy 1994-10, Vol.5 (5), p.304-311
• Main Authors: Doshi, K. J., Boudinot, F. D., Gallo, J. M., Schinazi, R. F., Chu, C. K.
• Format: Article
• Language: English
• Subjects: Adenosine; Adenosine deaminase; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Biotransformation; Central nervous system; HIV; Human immunodeficiency virus; Intravenous administration; Lipophilic; Medical sciences; Nervous system; Nucleosides; Oral administration; Pharmacology. Drug treatments; Plasma; Prodrugs
• ISSN: 2040-2066; 0956-3202; 2040-2066
• DOI: 10.1177/095632029400500504

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-CI-ddP) for the targeting of ddl to the brain. In vitro studies indicated that the adenosine deaminase-mediated biotransformation of 6-CI-ddP to ddl was more rapid in mouse brain homogenate than in mouse serum. The brain distribution of 6-CI-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-CI-ddP or ddl. However, after oral administration of the 6-CI-ddP prodrug, significantly greater concentrations of ddl were seen in the brain compared to those found after oral administration of ddl. The brain:serum AUG 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-CI-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-CI-ddP yielded concentrations of ddl in the brain similar to those obtained following intravenous administration. The results of this study provide further evidence that 6-CI-ddP may be a useful prodrug for delivering ddl to the central nervous system, particularly after oral administration.