Brain Targeting of anti-HIV Nucleosides: Ether Prodrugs of 3′-Azido-2′,3′-Dideoxyuridine (AZdU) and 3′-Azido-3′-Deoxythymidine (AZT)

In an effort to increase the brain delivery of anti-HIV nucleosides, 5-0-benzyl and glucose derivatives of 3′-azido-2′,3′-dideoxyuridine (AZdU or CS-87) and 3′-azido-3′-deoxythymidine (AZT) were synthesized. In vitro stability and pharmacokinetic studies in mice were conducted with benzyl AZdU (BzlAZdU), benzyl AZT (BzlAZT), and glucose AZdU (GAZdU) prodrugs. In vitro studies indicated that the prodrugs were stable in phosphate buffer (pH 7.4), human serum and mouse serum. In mouse brain homogenate, the degradation half-lives for BzlAZdU, BzlAZT, and GAZdU were 1.66, 2.06, and 0.98 h, respectively, and in liver homogenate the degradation half-lives were 0.49, 0.29, and 1.97h, respectively. Following intravenous administration of BzlAZdU, BzlAZT, or GAZdU to mice, prodrug and parent drug concentrations were measured in serum and brain by HPLC, and pharmacokinetic parameters determined. The brain:serum area under the concentration time-curve (AUC) ratio, a parameter indicative of prodrug uptake into brain, was 0.55 for BzlAZdU and 0.56 for BzlAZT, compared to 0.05–0.08 when the parent drugs AZdU and AZT were administered intravenously. GAZdU had poor brain penetration, achieving brain concentrations of only 5% of the serum concentrations. Parent drug concentrations in brain were, for the most part, not detected after administration of any of the prodrugs. Consistent with in vitro data, it is apparent that the prodrugs were converted to metabolites other than the parent drug species.