ENHANCED BRAIN DELIVERY OF AN ANTI-HIV NUCLEOSIDE 2'-F-ARA-DDI BY XANTHINE-OXIDASE MEDIATED BIOTRANSFORMATION

In order to enhance the brain delivery of 2'-F-ara-ddI, 2'-F-ara-ddP 6 was synthesized and its in vitro and in vivo bioconversion reaction s tudied. For the study, a new efficient synthetic method for 2'-F-ara-d dP 6 was developed from 5-benzoyl-1,2-0-isopropylidene-3-deoxyribose 1 . For in vitro study 2'-F-ara-ddP was incubated in pH 2, mouse liver h omogenate, and mouse serum at 37-degrees-C. No degradation was observe d in pH 2 and serum, while in liver homogenate 2'-F-ara-ddP was almost completely converted to 2'-F-ara-ddI within 20 min (t1/2 = 3.54 min). In order to determine the role of xanthine oxidase in the conversion of 2'-F-ara-ddP to 2'-F-ara-ddI, in vitro studies were conducted in ph osphate buffer (pH 7.4) in the presence or absence of allopurinol, in which the half-lives of 2'-F-ara-ddP were 7.4 and 3.4 h, respectively, indicating the conversions were catalyzed by the xanthine oxidase. A similar experiment with aldehyde oxidase isolated from the human liver did not affect the biotransformation. The biotransformation was also detected in the brain homogenate, although the rate of conversion was low and incomplete. In order to assess the bioconversion in vivo, phar macokinetic studies of 2'-F-ara-ddP and 2'-F-ara-ddI were conducted in mice. The maximum serum concentrations of 2'-F-ara-ddI administered i tself and as 2'-F-ara-ddP reached 48.1 +/- 10.00 and 89.3 +/- 26.0 muM and were observed in 1 and 0.25 h, respectively. The data indicate th at 2'-F-ara-ddI is absorbed at a slower rate than that of 2'-F-ara-ddP . The bioavailability of the prodrug after oral administration was 60. 7 %. The concentration of 2'-F-ara-ddI following oral administration o f 2'-ara-ddI was close to the detection limits while 2'-F-ara-ddI was detected at significantly higher concentrations in the brain after ora l administration of 2'-F-ara-ddP. From this study, we have administere d the enhanced brain delivery of anti-HIV nucleoside utilizing an in v ivo biotransformation system.