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 '-O-benzyl and glucose derivatives of 3'-azido-2',3'-dideoxyuridine (A ZdU or CS-87) and 3'-azido-3'-deoxythymidine (AZT) were synthesized. I n vitro stability and pharmacokinetic studies in mice were conducted w ith benzyl AZdU (BzlAZdU), benzyl AZT (BzlAZT), and glucose AZdU (GAZd U) prodrugs. In vitro studies indicated that the prodrugs were stable in phosphate buffer (pH 7.4), human serum and mouse serum. In mouse br ain homogenate, the degradation half-lives for BzlAZdU, BzlAZT, and GA ZdU were 1.66, 2.06, and 0.98 h, respectively, and in liver homogenate the degradation half-lives were 0.49, 0.29, and 1.97 h, respectively. Following intravenous administration of BzlAZdU, BzlAZT, or GAZdU to mice, prodrug and parent drug concentrations were measured in serum an d 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 0.5 6 for BzlAZT, compared to 0.05-0.08 when the parent drugs AZdU and AZT were administered intravenously. GAZdU had poor brain penetration, ac hieving brain concentrations of only 5% of the serum concentrations. P arent drug concentrations in brain were, for the most part, not detect ed after administration of any of the prodrugs. Consistent with in vit ro data, it is apparent that the prodrugs were converted to metabolite s other than the parent drug species.