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氟达拉滨药理
Fludarabine
DRUG NAME: Fludarabine
SYNONYM(S): 9-B-D-arabinofuranosyl-2-fluoroadenine 5’-monophosphate, FAMP,
1 2,3
1
3
1,3
1
2-fluoro-ara-A Monophosphate, 2-fluoro-ara-AMP, fludarabine phosphate, NSC-312887
COMMON TRADE NAME(S): FLUDARA?
CLASSIFICATION: antimetabolite
1
Special pediatric considerations are noted when applicable, otherwise adult provisions apply.
MECHANISM OF ACTION:
Fludarabine phosphate is a synthetic fluorinated analog of the purine nucleoside antiviral agent vidarabine (ara-A).1,4
1
Unlike vidarabine, fludarabine phosphate is resistant to deamination by adenosine deaminase. Fludarabine
phosphate is a water-soluble prodrug that is rapidly dephosphorylated to 2-fluoro-vidarabine (2F-ara-A). 2F-ara-A is
actively transported into cells and is then rephosphorylated via deoxycytidine kinase to the active triphosphate
1
derivative 2F-ara-ATP. 2F-ara-ATP competitively inhibits DNA synthesis via inhibition of DNA polymerase,
1,5
ribonucleotide reductase, DNA primase, and DNA ligase. 2F-ara-ATP prevents elongation of DNA strands through
1,2
direct incorporation into DNA as a false nucleotide. Partial inhibition of RNA polymerase II and resultant reduction
1
4
in protein synthesis may also occur. Cytotoxicity occurs primarily in the S-phase of cell division ; fludarabine is also
4
active against non-proliferating cells. Fludarabine has been shown to induce apoptosis in vitro.
1,6
PHARMACOKINETICS:
IV and oral dosing provide similar systemic exposure
6
6
Oral Absorption
Distribution
50-75%2,6,7; dose-independant, unaffected by food8
widely distributed3
cross blood brain barrier?
volume of distribution3
no information found
2
83-98 L/m ; suggests significant degree of tissue
binding
plasma protein binding
no in vivo information found
Metabolism
Excretion
rapidly and completely dephosphorylated in plasma to 2-F-ara-A; pharmacokinetic data is
based on 2F-ara-A
active metabolite(s)
2F-ara-ATP
inactive metabolite(s)2,9
2
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