Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.5.4.4 (
adenosine deaminase
)
5,136
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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.
...
PMID:Synthesis, biotransformation, and pharmacokinetic studies of 9-(beta-D-arabinofuranosyl)-6-azidopurine: a prodrug for ara-A designed to utilize the azide reduction pathway. 897 48
This study determined that the effect of 9-beta-d-arabinofuranosyl-adenine (adenine arabinoside,
Ara-A
) upon vaccinia virus plaque development in the stable monkey kidney line, LLC-MK(2), was increased approximately 40-fold when an inhibitor of
adenosine deaminase
(
ADA
) was added to the tissue culture media along with infective inocula. The concentration of
Ara-A
required to completely suppress plaque development (total plaque inhibitory concentration(100); TPIC(100)) was greater than 10 mug/ml. However, when
ADA
activity was inhibited, the TPIC(100) was 0.5 mug/ml or less. Chromatographic assay of arabinosylpurines in the media provided evidence that adenine arabinoside was rapidly deaminated to 9-beta-d-arabinofuranosylhypoxanthine by the cellular monolayers, in the absence of animal serum, and that the rate of deamination, at 5 mug/ml, by the cells was equal to the rate of diffusion of
Ara-A
across the cellular membrane. The half-life of
Ara-A
in the media, starting with 5 mug/ml, was 2 to 3 h and shorter at lower concentrations. The study demonstrates the profound effect that an indicator system, acting as an intact biological unit, can have upon a potential antiviral compound.
...
PMID:Effect of adenosine deaminase upon the antiviral activity in vitro of adenine arabinoside for vaccinia virus. 1582 18
<< Previous
1
2
