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Identification
Name Fludarabine
Accession Number DB01073 (APRD00594)
Type small molecule
Groups approved
Description

Fludarabine (marketed as fludarabine phosphate under the trade name Fludara) is a chemotherapy drug used in the treatment of hematological malignancies. [Wikipedia]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • FAMP
  • Fludarabine 5'-monophosphate
  • Fludarabine monophosphate
  • Fludarabine phosphate
Brand names
  • Fludara
  • Fludura
Brand name mixtures Not Available
Categories
  • Antineoplastic Agents
  • Antimetabolites
  • Immunosuppressive Agents
  • Antimetabolites, Antineoplastic
CAS number 75607-67-9
Weight Average: 365.2117
Monoisotopic: 365.053662512
Chemical Formula C10H13FN5O7P
InChI Key InChIKey=GIUYCYHIANZCFB-FJFJXFQQSA-N
InChI
InChI=1S/C10H13FN5O7P/c11-10-14-7(12)4-8(15-10)16(2-13-4)9-6(18)5(17)3(23-9)1-22-24(19,20)21/h2-3,5-6,9,17-18H,1H2,(H2,12,14,15)(H2,19,20,21)/t3-,5-,6+,9-/m1/s1
Plain Text
IUPAC Name
{[(2R,3S,4S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy}phosphonic acid
SMILES
NC1=NC(F)=NC2=C1N=CN2[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Not Available
Classes
  • Purines and Purine Derivatives
  • Carbohydrates
Substructures
  • Glycerol and Derivatives
  • Hydroxy Compounds
  • Phosphonic Acids and Derivatives
  • Organophosphate Esters
  • Aliphatic and Aryl Amines
  • Ethers
  • Pyrimidines and Derivatives
  • Alcohols and Polyols
  • Imidazoles
  • Heterocyclic compounds
  • Aromatic compounds
  • Purines and Purine Derivatives
  • Phosphinic Acids and Derivatives
  • Furans
  • Cyanamides
  • Aryl Halides
  • Carbohydrates
Pharmacology
Indication For the treatment of adult patients with B-cell chronic lymphocytic leukemia (CLL) who have not responded to or whose disease has progressed during treatment with at least one standard alkylating-agent containing regimen
Pharmacodynamics Fludarabine is a chemotherapy drug used in the treatment of chronic lymphocytic leukemia. It acts at DNA polymerase alpha, ribonucleotide reductase and DNA primase, results in the inhibition of DNA synthesis, and destroys the cancer cells.
Mechanism of action Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A and then phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate, 2-fluoro-ara-ATP. This metabolite appears to act by inhibiting DNA polymerase alpha, ribonucleotide reductase and DNA primase, thus inhibiting DNA synthesis. The mechanism of action of this antimetabolite is not completely characterized and may be multi-faceted.
Absorption Bioavailability is 55% following oral administration.
Volume of distribution Not Available
Protein binding 19-29%
Metabolism
Route of elimination Not Available
Half life 20 hours
Clearance
  • 117-145 mL/min [patients with B-cell CLL receiving IV administration of a single dose of 40 mg/m2]
Toxicity Not Available
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Genzyme corp
  • Actavis totowa llc
  • App pharmaceuticals llc
  • Hospira inc
  • Sandoz inc
  • Teva parenteral medicines inc
  • Sanofi aventis us llc
Packagers
Dosage forms
Form Route Strength
Powder, for solution Intravenous
Tablet Oral
Prices
Unit description Cost Unit
Fludara 50 mg vial 367.02 USD vial
Fludarabine 50 mg vial 240.0 USD vial
Oforta 10 mg tablet 92.57 USD tablet
Patents
Country Patent Number Approved Expires
United States 7148207 2002-12-20 2022-12-20
United States 7547776 1998-12-10 2018-12-10
Properties
State solid
Melting point 260 oC
Experimental Properties
Property Value Source
water solubility 3.53 mg/ml PhysProp
logP -2.8 PhysProp
Predicted Properties
Property Value Source
water solubility 2.97e+00 g/l ALOGPS
logP -2.51 ALOGPS
logP -3.97 ChemAxon Molconvert
logS -2.09 ALOGPS
pKa 6.26 ChemAxon Molconvert
hydrogen acceptor count 10 ChemAxon Molconvert
hydrogen donor count 5 ChemAxon Molconvert
polar surface area 186.07 ChemAxon Molconvert
rotatable bond count 4 ChemAxon Molconvert
refractivity 74.93 ChemAxon Molconvert
polarizability 28.88 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Rai KR, Peterson BL, Appelbaum FR, Kolitz J, Elias L, Shepherd L, Hines J, Threatte GA, Larson RA, Cheson BD, Schiffer CA: Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med. 2000 Dec 14;343(24):1750-7. Pubmed
  2. Gonzalez H, Leblond V, Azar N, Sutton L, Gabarre J, Binet JL, Vernant JP, Dighiero G: Severe autoimmune hemolytic anemia in eight patients treated with fludarabine. Hematol Cell Ther. 1998 Jun;40(3):113-8. Pubmed
  3. Tournilhac O, Cazin B, Lepretre S, Divine M, Maloum K, Delmer A, Grosbois B, Feugier P, Maloisel F, Villard F, Villemagne B, Bastit D, Belhadj K, Azar N, Michallet M, Manhes G, Travade P: Impact of frontline fludarabine and cyclophosphamide combined treatment on peripheral blood stem cell mobilization in B-cell chronic lymphocytic leukemia. Blood. 2004 Jan 1;103(1):363-5. Epub 2003 Sep 11. Pubmed
External Links
Resource Link
KEGG Drug D01907 Link_out
PubChem Compound 30751 Link_out
PubChem Substance 46507525 Link_out
ChemSpider 28532 Link_out
Therapeutic Targets Database DAP000567 Link_out
PharmGKB PA449655 Link_out
Drug Product Database 2246226 Link_out
RxList http://www.rxlist.com/cgi/generic/fludarabine.htm Link_out
Drugs.com http://www.drugs.com/cdi/fludarabine.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Fludarabine Link_out
ATC Codes
  • L01BB05
AHFS Codes
  • 10:00.00
PDB Entries Not Available
FDA label Not Available
MSDS show (48.1 KB)
Interactions
Drug Interactions Not Available
Food Interactions
  • Food slightly increases product bioavailability.
  • Take without regard to meals.
Targets

1. Ribonucleoside-diphosphate reductase large subunit

Pharmacological action: yes
Actions: inhibitor

Provides the precursors necessary for DNA synthesis. Catalyzes the biosynthesis of deoxyribonucleotides from the corresponding ribonucleotides

Organism class: human
UniProt ID: P23921 Link_out
Gene: RRM1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Lech-Maranda E, Korycka A, Robak T: Clofarabine as a novel nucleoside analogue approved to treat patients with haematological malignancies: mechanism of action and clinical activity. Mini Rev Med Chem. 2009 Jun;9(7):805-12. Pubmed
  4. Robak T, Korycka A, Lech-Maranda E, Robak P: Current status of older and new purine nucleoside analogues in the treatment of lymphoproliferative diseases. Molecules. 2009 Mar 23;14(3):1183-226. Pubmed

2. DNA polymerase alpha catalytic subunit

Pharmacological action: yes
Actions: inhibitor

Polymerase alpha in a complex with DNA primase is a replicative polymerase

Organism class: human
UniProt ID: P09884 Link_out
Gene: POLA1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Lech-Maranda E, Korycka A, Robak T: Clofarabine as a novel nucleoside analogue approved to treat patients with haematological malignancies: mechanism of action and clinical activity. Mini Rev Med Chem. 2009 Jun;9(7):805-12. Pubmed
  4. Robak T, Korycka A, Lech-Maranda E, Robak P: Current status of older and new purine nucleoside analogues in the treatment of lymphoproliferative diseases. Molecules. 2009 Mar 23;14(3):1183-226. Pubmed
  5. Robak T, Lech-Maranda E, Korycka A, Robak E: Purine nucleoside analogs as immunosuppressive and antineoplastic agents: mechanism of action and clinical activity. Curr Med Chem. 2006;13(26):3165-89. Pubmed

3. DNA

Pharmacological action: yes
Actions: incorporation into and destabilization

DNA is the molecule of heredity, as it is responsible for the genetic propagation of most inherited traits. It is a polynucleic acid that carries genetic information on cell growth, division, and function. DNA consists of two long strands of nucleotides twisted into a double helix and held together by hydrogen bonds. The sequence of nucleotides determines hereditary characteristics. Each strand serves as the template for subsequent DNA replication and as a template for mRNA production, leading to protein synthesis via ribosomes.

Gene Sequence: FASTA

References:
  1. Robak T, Lech-Maranda E, Korycka A, Robak E: Purine nucleoside analogs as immunosuppressive and antineoplastic agents: mechanism of action and clinical activity. Curr Med Chem. 2006;13(26):3165-89. Pubmed

4. Deoxycytidine kinase

Pharmacological action: yes
Actions: agonist

Required for the phosphorylation of several deoxyribonucleosides and certain nucleoside analogs widely employed as antiviral and chemotherapeutic agents

Organism class: human
UniProt ID: P27707 Link_out
Gene: DCK
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Jordheim LP, Galmarini CM, Dumontet C: [Metabolism, mechanism of action and resistance to cytotoxic nucleoside analogues] Bull Cancer. 2005 Mar;92(3):239-48. Pubmed
  2. Yao L, Xu W, Fan L, Miao KR, Wu YJ, Qiao C, Zhu DX, Zhu HY, Liu P, Li JY: [Correlation of deoxycytidine kinase gene expression with fludarabine resistance in patients with chronic lymphocytic leukemia] Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2010 Feb;18(1):36-9. Pubmed
  3. Zhang Y, Secrist JA 3rd, Ealick SE: The structure of human deoxycytidine kinase in complex with clofarabine reveals key interactions for prodrug activation. Acta Crystallogr D Biol Crystallogr. 2006 Feb;62(Pt 2):133-9. Epub 2006 Jan 18. Pubmed
Transporters

1. Equilibrative nucleoside transporter 1

Actions: substrate

Mediates both influx and efflux of nucleosides across the membrane (equilibrative transporter). It is sensitive (ES) to low concentrations of the inhibitor nitrobenzylmercaptopurine riboside (NBMPR) and is sodium-independent. It has a higher affinity for adenosine. Inhibited by dipyridamole and dilazep (anticancer chemotherapeutics drugs)

UniProt ID: Q99808 Link_out
Gene: SLC29A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Santini D, Vincenzi B, Fratto ME, Perrone G, Lai R, Catalano V, Cass C, Ruffini PA, Spoto C, Muretto P, Rizzo S, Muda AO, Mackey JR, Russo A, Tonini G, Graziano F: Prognostic role of human equilibrative transporter 1 (hENT1) in patients with resected gastric cancer. J Cell Physiol. 2010 May;223(2):384-8. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on October 05, 2011 16:18

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.