Fludarabine

Identification

Summary

Fludarabine is a purine analog antimetabolite that inhibits DNA synthesis.

Brand Names
Fludara
Generic Name
Fludarabine
DrugBank Accession Number
DB01073
Background

Fludarabine is a chemotherapeutic agent used in the treatment of hematological malignancies. It is commonly marketed under the brand name Fludara.

Type
Small Molecule
Groups
Approved
Structure
Weight
Average: 285.235
Monoisotopic: 285.087332049
Chemical Formula
C10H12FN5O4
Synonyms
  • 2-F-ARAA
  • 2-fluoro ARA-A
  • Fludarabina
  • Fludarabine
  • Fludarabinum
External IDs
  • NSC-118218
  • NSC-118218H

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

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofRefractory b-cell chronic lymphocytic leukemia••••••••••••
Treatment ofRefractory non-hodgkin's lymphoma••••••••••••
Contraindications & Blackbox Warnings
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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.

TargetActionsOrganism
ADNA
incorporation into and destabilization
Humans
ADeoxycytidine kinase
agonist
Humans
ADNA polymerase alpha catalytic subunit
inhibitor
Humans
ARibonucleoside-diphosphate reductase large subunit
inhibitor
Humans
Absorption

Bioavailability is 55% following oral administration.

Volume of distribution

Not Available

Protein binding

19-29%

Metabolism
Not Available
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/m^2.
Adverse Effects
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Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbataceptThe risk or severity of adverse effects can be increased when Fludarabine is combined with Abatacept.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Fludarabine.
AcenocoumarolThe risk or severity of bleeding can be increased when Acenocoumarol is combined with Fludarabine.
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Fludarabine.
Acetylsalicylic acidThe risk or severity of bleeding can be increased when Acetylsalicylic acid is combined with Fludarabine.
Food Interactions
  • Take with or without food. Administration with food delays absorption, but not to a clinically significant extent.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Fludarabine phosphate1X9VK9O1SC75607-67-9GIUYCYHIANZCFB-FJFJXFQQSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
FludaraPowder, for solution50 mg / vialIntravenousSanofi Genzyme, a Division of Sanofi Aventis Canada Inc1993-12-312011-03-31Canada flag
FludaraTablet10 mgOralSanofi Aventis2002-09-24Not applicableCanada flag
FludaraInjection, powder, lyophilized, for solution50 mg/2mLIntravenousBayer1991-04-182013-06-30US flag
FludaraInjection, powder, lyophilized, for solution50 mg/2mLIntravenousGenzyme Corporation2010-07-292012-03-09US flag
Fludarabine PhosphateTablet, film coated10 mg/1OralAntisoma Research Limited2009-02-18Not applicableUS flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Aj-fludarabineSolution25.0 mg / mLIntravenousAgila Jamp Canada IncNot applicableNot applicableCanada flag
FludarabineInjection, powder, lyophilized, for solution25 mg/1mLIntravenousFresenius Kabi USA, LLC2009-12-112010-06-01US flag
FludarabineInjection, solution25 mg/1mLIntravenousFresenius Kabi USA, LLC2007-11-16Not applicableUS flag
Fludarabine PhosphateInjection25 mg/1mLIntravenousAreva Pharmaceuticals2019-12-31Not applicableUS flag
Fludarabine phosphateInjection, solution25 mg/1mLIntravenousActavis Pharma, Inc.2017-03-022023-06-30US flag
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
Fludarabine PhosphateFludarabine phosphate (25 mg/1mL)InjectionIntravenousAccord Healthcare, Inc.2022-11-22Not applicableUS flag
Fludarabine PhosphateFludarabine phosphate (25 mg/1mL)Injection, solutionIntravenousTeva Pharmaceuticals, Inc.2023-08-31Not applicableUS flag

Categories

ATC Codes
L01BB05 — Fludarabine
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This 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.
Kingdom
Organic compounds
Super Class
Nucleosides, nucleotides, and analogues
Class
Purine nucleosides
Sub Class
Not Available
Direct Parent
Purine nucleosides
Alternative Parents
Glycosylamines / 6-aminopurines / Pentoses / 2-halopyrimidines / Aminopyrimidines and derivatives / Aryl fluorides / Imidolactams / N-substituted imidazoles / Heteroaromatic compounds / Tetrahydrofurans
show 8 more
Substituents
2-halopyrimidine / 6-aminopurine / Alcohol / Amine / Aminopyrimidine / Aromatic heteropolycyclic compound / Aryl fluoride / Aryl halide / Azacycle / Azole
show 27 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
P2K93U8740
CAS number
21679-14-1
InChI Key
HBUBKKRHXORPQB-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[C@H](CO)[C@@H](O)[C@@H]1O

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. [Article]
  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. [Article]
  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. [Article]
KEGG Drug
D01907
PubChem Compound
657237
PubChem Substance
46507525
ChemSpider
571392
BindingDB
68391
RxNav
24698
ChEBI
94701
ChEMBL
CHEMBL1568
ZINC
ZINC000004216238
Therapeutic Targets Database
DAP000567
PharmGKB
PA449655
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Fludarabine
MSDS
Download (48.1 KB)

Clinical Trials

Clinical Trials

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • APP Pharmaceuticals
  • Bayer Healthcare
  • Ben Venue Laboratories Inc.
  • Ebewe Pharma
  • Genzyme Inc.
  • Hospira Inc.
  • Sagent Pharmaceuticals
  • Sanofi-Aventis Inc.
  • Sicor Pharmaceuticals
  • Teva Pharmaceutical Industries Ltd.
Dosage Forms
FormRouteStrength
SolutionIntravenous25.0 mg / mL
SolutionParenteral50 mg
TabletOral10.000 mg
Injection, powder, lyophilized, for solutionIntravenous50 mg/2mL
Powder, for solutionIntravenous50 mg / vial
TabletOral10 mg
Tablet, film coatedOral
Tablet, film coatedOral10 mg
InjectionIntravenous
Tablet, coatedOral10 mg
Injection, solutionParenteral25 mg/ml
Solution, concentrateParenteral25 MG/ML
Injection, powder, for solutionIntravenous50 MG
Injection, powder, lyophilized, for solutionIntravenous50 mg
Injection, powder, for solutionIntravenous
Solution, concentrate
Solution, concentrateIntravenous50 mg
Injection, powder, lyophilized, for solutionIntravenous
InjectionIntravenous25 mg/1mL
Injection, powder, lyophilized, for solutionIntravenous25 mg/1mL
Injection, solutionIntravenous25 mg/1mL
Tablet, film coatedOral10 mg/1
SolutionIntravenous25 mg / mL
LiquidIntravenous25 mg / mL
Injection, solution, concentrateParenteral50 mg/2ml
SolutionIntravenous50 mg/2ml
Injection, solutionIntravenous50 mg/2ml
SolutionIntravenous200.00 mg
Powder50 mg/1vial
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)Region
US7148207No2006-12-122022-12-20US flag
US7547776No2009-06-162018-12-10US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)260 °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)0.76Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count8Chemaxon
Hydrogen Donor Count4Chemaxon
Polar Surface Area139.54 Å2Chemaxon
Rotatable Bond Count2Chemaxon
Refractivity64.06 m3·mol-1Chemaxon
Polarizability25.33 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
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)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-00r6-9670000000-e6d91df945dc377e1539
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSsplash10-0059-0359000000-0759bfeee68a8abd65e2
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSsplash10-0udi-3900000000-5f778f763f3c6e93fd1e
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0udi-1920000000-6e5e3aa285e922e0f04a
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0udi-3900000000-5f778f763f3c6e93fd1e
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-000i-0090000000-f9484f5e4b51b55d9a93
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-001i-0900000000-40481befad2946abb9a7
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0udi-0900000000-fc6daaef2dafb496b220
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0ue9-0900000000-cfceb00461caa245786e
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0udi-0910000000-71a05f32fa5f1744df09
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-001i-0910000000-547423d675d8f8e9679e
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-157.43149
predicted
DeepCCS 1.0 (2019)
[M+H]+159.82704
predicted
DeepCCS 1.0 (2019)
[M+Na]+166.80373
predicted
DeepCCS 1.0 (2019)

Targets

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Use our structured and evidence-based datasets to unlock new
insights and accelerate drug research.
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Kind
Nucleotide
Organism
Humans
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.
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. [Article]
Kind
Protein
Organism
Humans
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...
Gene Name
DCK
Uniprot ID
P27707
Uniprot Name
Deoxycytidine kinase
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. [Article]
  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. [Article]
  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. [Article]
Kind
Protein
Organism
Humans
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 subuni...
Gene Name
POLA1
Uniprot ID
P09884
Uniprot Name
DNA polymerase alpha catalytic subunit
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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
Kind
Protein
Organism
Humans
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
Uniprot Name
Ribonucleoside-diphosphate reductase large subunit
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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]

Transporters

Kind
Protein
Organism
Humans
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...
Gene Name
SLC29A1
Uniprot ID
Q99808
Uniprot Name
Equilibrative nucleoside transporter 1
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. [Article]
Kind
Protein
Organism
Humans
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 subtyp...
Gene Name
SLC28A3
Uniprot ID
Q9HAS3
Uniprot Name
Solute carrier family 28 member 3
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. [Article]

Drug created at June 13, 2005 13:24 / Updated at March 18, 2024 16:48