Synthesis, biotransformation, and pharmacokinetic studies of 9-(beta-D-arabinofuranosyl)-6-azidopurine: a prodrug for ara-A designed to utilize the azide reduction pathway.
As a part of our efforts to design prodrugs for antiviral nucleosides, 9-(beta-D-arabinofuranosyl)-6-azidopurine (6-AAP) was synthesized as a prodrug for ara-A that utilizes the azide reduction biotransformation pathway. 6-AAP was synthesized from ara-A via its 6-chloro analogue 4. The bioconversion of the prodrug was investigated in vitro and in vivo, and the pharmacokinetic parameters were determined. For in vitro studies, 6-AAP was incubated in mouse serum and liver and brain homogenates. The half-lives of 6-AAP in serum and liver and brain homogenates were 3.73, 4.90, and 7.29 h, respectively. 6-AAP was metabolized primarily in the liver homogenate microsomal fraction by the reduction of the azido moiety to the amine, yielding ara-A. However, 6-AAP was found to be stable to adenosine deaminase in a separate in vitro study. The in vivo metabolism and disposition of ara-A and 6-AAP were conducted in mice. When 6-AAP was administered by either oral or intravenous route,the half-life of ara-A was 7-14 times higher than for ara-A administered intravenously. Ara-A could not be found in the brain after the intravenous administration of ara-A. However, after 6-AAP administration (by either oral or intravenous route), significant levels of ara-A were found in the brain. The results of this study demonstrate that 6-AAP is converted to ara-A, potentially increasing the half-life and the brain delivery of ara-A. Further studies to utilize the azide reduction approach on other clinically useful agents containing an amino group are in progress in our laboratories.
Kotra
L P
LP
Department of Medicinal Chemistry, College of Pharmacy, University of Georgia, Athens 30602-2352, USA.
Manouilov
K K
KK
Cretton-Scott
E
E
Sommadossi
J P
JP
Boudinot
F D
FD
Schinazi
R F
RF
Chu
C K
CK
D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001386:Azides / Q000737:chemistry; D001711:Biotransformation; D001921:Brain / Q000378:metabolism; D005260:Female; D051379:Mice; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics*
D000998:Antiviral Agents; D001386:Azides; D011355:Prodrugs; C103091:9-arabinofuranosyl-6-azidopurine; D014740:Vidarabine