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Identification
NameFludarabine
Accession NumberDB01073  (APRD00594)
TypeSmall Molecule
GroupsApproved
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
Synonyms
2-F-ARAA
2-fluoro ARA-A
External Identifiers
  • NSC-118218
  • NSC-118218H
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Aj-fludarabinesolution25.0 mgintravenousAgila Jamp Canada IncNot applicableNot applicableCanada
Fludarapowder for solution50 mgintravenousGenzyme Canada A Division Of Sanofi Aventis Canada Inc1993-12-312011-03-31Canada
Fludaratablet10 mgoralSanofi Aventis Canada Inc2002-09-24Not applicableCanada
Fludarabine Phosphateinjection, solution25 mg/mLintravenousSandoz Inc2007-10-12Not applicableUs
Fludarabine Phosphate for Injectionpowder for solution50 mgintravenousFresenius Kabi Canada LtdNot applicableNot applicableCanada
Fludarabine Phosphate for Injectionsolution25 mgintravenousTeva Canada Limited2006-12-04Not applicableCanada
Fludarabine Phosphate for Injection USPpowder for solution50 mgintravenousHospira Healthcare Corporation2008-09-22Not applicableCanada
Fludarabine Phosphate Injectionliquid25 mgintravenousOmega Laboratories LtdNot applicableNot applicableCanada
Fludarabine Phosphate Injectionsolution25 mgintravenousMylan Pharmaceuticals UlcNot applicableNot applicableCanada
Fludarabine Phosphate Injectionsolution25 mgintravenousFresenius Kabi Canada Ltd2011-04-11Not applicableCanada
Fludarabine Phosphate Injection, USPsolution25 mgintravenousAccord Healthcare IncNot applicableNot applicableCanada
Approved Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Fludarabineinjection, powder, lyophilized, for solution25 mg/mLintravenousAPP Pharmaceuticals, LLC2009-12-11Not applicableUs
Fludarabineinjection, solution25 mg/mLintravenousAPP Pharmaceuticals, LLC2007-11-16Not applicableUs
Fludarabine Phosphateinjection25 mg/mLintravenousPfizer Laboratories Div Pfizer Inc.2011-12-22Not applicableUs
Fludarabine Phosphateinjection, powder, lyophilized, for solution50 mg/2mLintravenousHospira Worldwide, Inc.2007-04-06Not applicableUs
Fludarabine Phosphateinjection, powder, lyophilized, for solution50 mg/2mLintravenousActavis Pharma, Inc.2015-01-05Not applicableUs
Fludarabine Phosphateinjection, powder, lyophilized, for solution25 mg/mLintravenousSagent Pharmaceuticals2014-12-15Not applicableUs
Fludarabine Phosphateinjection25 mg/mLintravenousMylan Institutional LLC2011-12-22Not applicableUs
Fludarabine Phosphateinjection, powder, lyophilized, for solution50 mg/2mLintravenousSagent Pharmaceuticals2009-02-01Not applicableUs
Fludarabine Phosphateinjection, solution25 mg/mLintravenousMylan Institutional LLC2013-01-30Not applicableUs
Fludarabine Phosphateinjection, powder, lyophilized, for solution50 mg/2mLintravenousTeva Parenteral Medicines, Inc.2003-09-12Not applicableUs
Fludarabine Phosphateinjection, solution25 mg/mLintravenousMylan Institutional LLC2013-01-30Not applicableUs
Fludarabine Phosphateinjection, solution25 mg/mLintravenousTeva Parenteral Medicines, Inc.2004-05-01Not applicableUs
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
FluduraNot Available
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Fludarabine phosphate
75607-67-9
Thumb
  • InChI Key: GIUYCYHIANZCFB-FJFJXFQQSA-N
  • Monoisotopic Mass: 365.053662512
  • Average Mass: 365.2117
DBSALT000425
Categories
UNIIP2K93U8740
CAS number21679-14-1
WeightAverage: 285.235
Monoisotopic: 285.087332049
Chemical FormulaC10H12FN5O4
InChI KeyHBUBKKRHXORPQB-FJFJXFQQSA-N
InChI
InChI=1S/C10H12FN5O4/c11-10-14-7(12)4-8(15-10)16(2-13-4)9-6(19)5(18)3(1-17)20-9/h2-3,5-6,9,17-19H,1H2,(H2,12,14,15)/t3-,5-,6+,9-/m1/s1
IUPAC Name
(2R,3S,4S,5R)-2-(6-amino-2-fluoro-9H-purin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol
SMILES
NC1=NC(F)=NC2=C1N=CN2[C@@H]1O[[email protected]](CO)[C@@H](O)[C@@H]1O
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as purine nucleosides. These are compounds comprising a purine base attached to a ribosyl or deoxyribosyl moiety.
KingdomOrganic compounds
Super ClassNucleosides, nucleotides, and analogues
ClassPurine nucleosides
Sub ClassNot Available
Direct ParentPurine nucleosides
Alternative Parents
Substituents
  • Purine nucleoside
  • Glycosyl compound
  • N-glycosyl compound
  • 6-aminopurine
  • Pentose monosaccharide
  • Imidazopyrimidine
  • Purine
  • Aminopyrimidine
  • 2-halopyrimidine
  • Halopyrimidine
  • Aryl fluoride
  • Aryl halide
  • Monosaccharide
  • N-substituted imidazole
  • Imidolactam
  • Pyrimidine
  • Oxolane
  • Azole
  • Heteroaromatic compound
  • Imidazole
  • Secondary alcohol
  • Organoheterocyclic compound
  • Oxacycle
  • Azacycle
  • Organohalogen compound
  • Organooxygen compound
  • Organofluoride
  • Hydrocarbon derivative
  • Organonitrogen compound
  • Alcohol
  • Organic nitrogen compound
  • Primary alcohol
  • Primary amine
  • Amine
  • Organic oxygen compound
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationFor 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
PharmacodynamicsFludarabine 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 actionFludarabine 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.
Related Articles
AbsorptionBioavailability is 55% following oral administration.
Volume of distributionNot Available
Protein binding19-29%
MetabolismNot Available
Route of eliminationNot Available
Half life20 hours
Clearance
  • 117-145 mL/min [patients with B-cell CLL receiving IV administration of a single dose of 40 mg/m2]
ToxicityNot Available
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption-0.5639
Blood Brain Barrier+0.9233
Caco-2 permeable-0.7128
P-glycoprotein substrateNon-substrate0.6729
P-glycoprotein inhibitor INon-inhibitor0.8877
P-glycoprotein inhibitor IINon-inhibitor0.9758
Renal organic cation transporterNon-inhibitor0.9454
CYP450 2C9 substrateNon-substrate0.879
CYP450 2D6 substrateNon-substrate0.8252
CYP450 3A4 substrateNon-substrate0.5202
CYP450 1A2 substrateNon-inhibitor0.7718
CYP450 2C9 inhibitorNon-inhibitor0.8907
CYP450 2D6 inhibitorNon-inhibitor0.8648
CYP450 2C19 inhibitorNon-inhibitor0.8716
CYP450 3A4 inhibitorNon-inhibitor0.8466
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9276
Ames testNon AMES toxic0.7735
CarcinogenicityNon-carcinogens0.8925
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.2806 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.98
hERG inhibition (predictor II)Non-inhibitor0.7675
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage forms
FormRouteStrength
Solutionintravenous25.0 mg
Tabletoral10 mg
Injectionintravenous25 mg/mL
Injection, powder, lyophilized, for solutionintravenous25 mg/mL
Injection, powder, lyophilized, for solutionintravenous50 mg/2mL
Injection, solutionintravenous25 mg/mL
Solutionintravenous25 mg
Powder for solutionintravenous50 mg
Liquidintravenous25 mg
Prices
Unit descriptionCostUnit
Fludara 50 mg vial367.02USD vial
Fludarabine 50 mg vial240.0USD vial
Oforta 10 mg tablet92.57USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7148207 No2002-12-202022-12-20Us
US7547776 No1998-12-102018-12-10Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point260 °CNot Available
water solubility3.53 mg/mlNot Available
logP-2.8Not Available
Predicted Properties
PropertyValueSource
Water Solubility12.1 mg/mLALOGPS
logP-0.62ALOGPS
logP-1.5ChemAxon
logS-1.4ALOGPS
pKa (Strongest Acidic)12.45ChemAxon
pKa (Strongest Basic)0.71ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area139.54 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity64.06 m3·mol-1ChemAxon
Polarizability25.16 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

John G. Bauman, Randolph C. Wirsching, “Process for the preparation of fludarabine or fludarabine phosphate from guanosine.” U.S. Patent US5602246, issued January, 1992.

US5602246
General References
  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:11114313 ]
  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:9698219 ]
  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:12969985 ]
External Links
ATC CodesL01BB05
AHFS Codes
  • 10:00.00
PDB EntriesNot Available
FDA labelNot Available
MSDSDownload (48.1 KB)
Interactions
Drug Interactions
Drug
ClozapineThe risk or severity of adverse effects can be increased when Fludarabine is combined with Clozapine.
DenosumabThe risk or severity of adverse effects can be increased when Denosumab is combined with Fludarabine.
ImatinibImatinib may decrease the myelosuppressive activities of Fludarabine.
LeflunomideThe risk or severity of adverse effects can be increased when Fludarabine is combined with Leflunomide.
MetamizoleThe risk or severity of adverse effects can be increased when Metamizole is combined with Fludarabine.
NatalizumabThe risk or severity of adverse effects can be increased when Fludarabine is combined with Natalizumab.
PentostatinThe risk or severity of adverse effects can be increased when Fludarabine is combined with Pentostatin.
PimecrolimusThe risk or severity of adverse effects can be increased when Pimecrolimus is combined with Fludarabine.
RoflumilastRoflumilast may increase the immunosuppressive activities of Fludarabine.
Sipuleucel-TThe therapeutic efficacy of Sipuleucel-T can be decreased when used in combination with Fludarabine.
TacrolimusThe risk or severity of adverse effects can be increased when Tacrolimus is combined with Fludarabine.
TofacitinibFludarabine may increase the immunosuppressive activities of Tofacitinib.
TrastuzumabTrastuzumab may increase the neutropenic activities of Fludarabine.
Food Interactions
  • Food slightly increases product bioavailability.
  • Take without regard to meals.

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Protein kinase binding
Specific Function:
Plays an essential role in the initiation of DNA replication. During the S phase of the cell cycle, the DNA polymerase alpha complex (composed of a catalytic subunit POLA1/p180, a regulatory subunit POLA2/p70 and two primase subunits PRIM1/p49 and PRIM2/p58) is recruited to DNA at the replicative forks via direct interactions with MCM10 and WDHD1. The primase subunit of the polymerase alpha com...
Gene Name:
POLA1
Uniprot ID:
P09884
Molecular Weight:
165911.405 Da
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:17139284 ]
  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:17016423 ]
  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:19519505 ]
  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. doi: 10.3390/molecules14031183. [PubMed:19325518 ]
  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:17168705 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Ribonucleoside-diphosphate reductase activity, thioredoxin disulfide as acceptor
Specific Function:
Provides the precursors necessary for DNA synthesis. Catalyzes the biosynthesis of deoxyribonucleotides from the corresponding ribonucleotides.
Gene Name:
RRM1
Uniprot ID:
P23921
Molecular Weight:
90069.375 Da
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:17139284 ]
  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:17016423 ]
  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:19519505 ]
  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. doi: 10.3390/molecules14031183. [PubMed:19325518 ]
3. DNA
Kind
Nucleotide
Organism
Human
Pharmacological action
yes
Actions
incorporation into and destabilization
General Function:
Used for biological information storage.
Specific Function:
DNA contains the instructions needed for an organism to develop, survive and reproduce.
Molecular Weight:
2.15 x 1012 Da
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:17168705 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
agonist
General Function:
Protein homodimerization activity
Specific Function:
Required for the phosphorylation of the deoxyribonucleosides deoxycytidine (dC), deoxyguanosine (dG) and deoxyadenosine (dA). Has broad substrate specificity, and does not display selectivity based on the chirality of the substrate. It is also an essential enzyme for the phosphorylation of numerous nucleoside analogs widely employed as antiviral and chemotherapeutic agents.
Gene Name:
DCK
Uniprot ID:
P27707
Molecular Weight:
30518.315 Da
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:15820918 ]
  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:20137114 ]
  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:16421443 ]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Nucleoside transmembrane transporter activity
Specific Function:
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).
Gene Name:
SLC29A1
Uniprot ID:
Q99808
Molecular Weight:
50218.805 Da
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. doi: 10.1002/jcp.22045. [PubMed:20082300 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Pyrimidine- and adenine-specific:sodium symporter activity
Specific Function:
Sodium-dependent, pyrimidine- and purine-selective. Involved in the homeostasis of endogenous nucleosides. Exhibits the transport characteristics of the nucleoside transport system cib or N3 subtype (N3/cib) (with marked transport of both thymidine and inosine). Employs a 2:1 sodium/nucleoside ratio. Also able to transport gemcitabine, 3'-azido-3'-deoxythymidine (AZT), ribavirin and 3-deazaurid...
Gene Name:
SLC28A3
Uniprot ID:
Q9HAS3
Molecular Weight:
76929.61 Da
References
  1. Badagnani I, Chan W, Castro RA, Brett CM, Huang CC, Stryke D, Kawamoto M, Johns SJ, Ferrin TE, Carlson EJ, Burchard EG, Giacomini KM: Functional analysis of genetic variants in the human concentrative nucleoside transporter 3 (CNT3; SLC28A3). Pharmacogenomics J. 2005;5(3):157-65. [PubMed:15738947 ]
Comments
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Drug created on June 13, 2005 07:24 / Updated on May 28, 2016 02:12