氟达拉滨药理.docVIP

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