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M9490062.TXT
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1994-09-03
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Document 0062
DOCN M9490062
TI Adamantane as a brain-directed drug carrier for poorly absorbed drug. 2.
AZT derivatives conjugated with the 1-adamantane moiety.
DT 9411
AU Tsuzuki N; Hama T; Kawada M; Hasui A; Konishi R; Shiwa S; Ochi Y; Futaki
S; Kitagawa K; Telkoku Seiyaku Company Ltd., Kagawa, Japan.
SO J Pharm Sci. 1994 Apr;83(4):481-4. Unique Identifier : AIDSLINE
MED/94322211
AB Five AZT (azidothymidine) prodrugs conjugated with the 1-adamantane
moiety via an ester bond were synthesized to improve the transport of
AZT into the central nervous system (CNS). In in vitro degradation
studies with rat and human plasma, it was demonstrated that the prodrugs
were degraded enzymatically and converted quantitatively to their parent
drug. AZT. As assessed by octanol-buffer partitioning, the prodrugs were
much more lipophilic than AZT and were expected to penetrate the
blood-brain barrier (BBB) readily. In in vivo studies, in which the
prodrugs were administered intravenously to rat, the prodrugs in brain
tissue were detected at 7-18 times higher concentrations than AZT in
spite of the negligible amount of the prodrug in the cerebrospinal
fluid. These results indicate that the introduction to AZT of the
1-adamantane moiety results in the enhancement of the BBB penetration.
This pharmaceutical approach would be beneficial for the efficient
treatment of the CNS infection by human immunodeficiency virus.
DE Adamantane/*PHARMACOLOGY/PHARMACOKINETICS Animal Blood-Brain
Barrier/PHYSIOLOGY Brain/*METABOLISM Chemistry, Physical
Chromatography, High Pressure Liquid Drug Carriers Human Hydrolysis
In Vitro Male Prodrugs/CHEMICAL
SYNTHESIS/*PHARMACOLOGY/PHARMACOKINETICS Rats Rats, Wistar
Zidovudine/ANALOGS & DERIVATIVES/ADMINISTRATION & DOSAGE/
*PHARMACOKINETICS JOURNAL ARTICLE
SOURCE: National Library of Medicine. NOTICE: This material may be
protected by Copyright Law (Title 17, U.S.Code).