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Identification
NameClofarabine
Accession NumberDB00631  (APRD00878, DB07554)
TypeSmall Molecule
GroupsApproved, Investigational
Description

Clofarabine is a purine nucleoside antimetabolite that is being studied in the treatment of cancer. It is marketed in the U.S. and Canada as Clolar. In Europe and Australia/New Zealand the product is marketed under the name Evoltra.

Clofarabine is used in paediatrics to treat a type of leukaemia called relapsed or refractory acute lymphoblastic leukaemia (ALL), only after at least two other types of treatment have failed. It is not known if the drug extends life expectancy. Some investigations of effectiveness in cases of acute myeloid leukaemia (AML) and juvenile myelomonocytic leukaemia (JMML) have been carried out.

Structure
Thumb
Synonyms
SynonymLanguageCode
(2R,3R,4S,5R)-5-(6-amino-2-Chloropurin-9-yl)-4-fluoro-2-(hydroxymethyl)oxolan-3-olNot AvailableNot Available
2-chloro-9-(2-Deoxy-2-fluoro-beta-D-arabinofuranosyl)adenineNot AvailableNot Available
2-chloro-9-(2'-Deoxy-2'-fluoro-beta-D-arabinofuranosyl)adenineNot AvailableNot Available
CAFdANot AvailableNot Available
CL-F-Ara-aNot AvailableNot Available
ClofarabinGermanINN
ClofarabinaSpanishINN
ClofarabineFrenchINN
ClofarabinumLatinINN
ClofarexNot AvailableIS
ClolarNot AvailableIS
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Clolarinjection1 mg/mLintravenousSanofi Aventis U.S. Llc2013-04-01Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Clolarinjection1 mg/mLintravenousGenzyme Corporation2004-12-28Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Clolarsolution1 mgintravenousSanofi Aventis Canada IncNot AvailableNot AvailableCanada 5f16b84899037e23705f146ff57e3794121879cb055f0954756d94bc690476b4
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International Brands
NameCompany
ClofazicRaffo
EvoltraGenzyme
Brand mixturesNot Available
SaltsNot Available
Categories
CAS number123318-82-1
WeightAverage: 303.677
Monoisotopic: 303.053445155
Chemical FormulaC10H11ClFN5O3
InChI KeyWDDPHFBMKLOVOX-AYQXTPAHSA-N
InChI
InChI=1S/C10H11ClFN5O3/c11-10-15-7(13)5-8(16-10)17(2-14-5)9-4(12)6(19)3(1-18)20-9/h2-4,6,9,18-19H,1H2,(H2,13,15,16)/t3-,4+,6-,9-/m1/s1
IUPAC Name
(2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)oxolan-3-ol
SMILES
[H][C@]1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C=NC2=C(N)N=C(Cl)N=C12
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as purine 3'-deoxyribonucleosides. These are compounds consisting of a purine linked to a ribose which lacks a hydroxyl group at position 3.
KingdomOrganic compounds
Super ClassNucleosides, nucleotides, and analogues
ClassPurine nucleosides
Sub ClassPurine 3'-deoxyribonucleosides
Direct ParentPurine 3'-deoxyribonucleosides
Alternative Parents
Substituents
  • Purine 3'-deoxyribonucleoside
  • Purine 2'-deoxyribonucleoside
  • 6-aminopurine
  • Purine
  • Imidazopyrimidine
  • Halopyrimidine
  • Aminopyrimidine
  • Imidolactam
  • Pyrimidine
  • Primary aromatic amine
  • N-substituted imidazole
  • Aryl halide
  • Aryl chloride
  • Heteroaromatic compound
  • Oxolane
  • Imidazole
  • Azole
  • Secondary alcohol
  • Halohydrin
  • Fluorohydrin
  • Oxacycle
  • Azacycle
  • Organoheterocyclic compound
  • Hydrocarbon derivative
  • Primary amine
  • Primary alcohol
  • Organooxygen compound
  • Organonitrogen compound
  • Organofluoride
  • Organochloride
  • Organohalogen compound
  • Amine
  • Alkyl halide
  • Alkyl fluoride
  • Alcohol
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Pharmacology
IndicationFor the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphocytic (lymphoblastic) leukemia after at least two prior regimens. It is designated as an orphan drug by the FDA for this use.
PharmacodynamicsClofarabine is a purine nucleoside antimetabolite that differs from other puring nucleoside analogs by the presence of a chlorine in the purine ring and a flourine in the ribose moiety. Clofarabine seems to interfere with the growth of cancer cells, which are eventually destroyed. Since the growth of normal body cells may also be affected by clofarabine, other effects also occur. Clofarabine prevents cells from making DNA and RNA by interfering with the synthesis of nucleic acids, thus stopping the growth of cancer cells.
Mechanism of actionClofarabine is metabolized intracellularly to the active 5'-monophosphate metabolite by deoxycytidine kinase and 5'-triphosphate metabolite by mono- and di-phospho-kinases. This metabolite inhibits DNA synthesis through an inhibitory action on ribonucleotide reductase, and by terminating DNA chain elongation and inhibiting repair through competitive inhibition of DNA polymerases. This leads to the depletion of the intracellular deoxynucleotide triphosphate pool and the self-potentiation of clofarabine triphosphate incorporation into DNA, thereby intensifying the effectiveness of DNA synthesis inhibition. The affinity of clofarabine triphosphate for these enzymes is similar to or greater than that of deoxyadenosine triphosphate. In preclinical models, clofarabine has demonstrated the ability to inhibit DNA repair by incorporation into the DNA chain during the repair process. Clofarabine 5'-triphosphate also disrupts the integrity of mitochondrial membrane, leading to the release of the pro-apoptotic mitochondrial proteins, cytochrome C and apoptosis-inducing factor, leading to programmed cell death.
AbsorptionNot Available
Volume of distribution
  • 172 L/m2
Protein binding47% bound to plasma proteins, predominantly to albumin.
Metabolism

Clofarabine is sequentially metabolized intracellularly to the 5’-monophosphate metabolite by deoxycytidine kinase and mono- and di-phosphokinases to the active 5’-triphosphate metabolite. Clofarabine has high affinity for the activating phosphorylating enzyme, deoxycytidine kinase, equal to or greater than that of the natural substrate, deoxycytidine.

SubstrateEnzymesProduct
Clofarabine
clofarabind-5'-monophosphateDetails
Route of eliminationBased on 24-hour urine collections in the pediatric studies, 49 - 60% of the dose is excreted in the urine unchanged.
Half lifeThe terminal half-life is estimated to be 5.2 hours.
Clearance
  • 28.8 L/h/m2 [Pediatric patients (2 – 19 years old) with relapsed or refractory acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML) receiving 52 mg/m2 dose]
ToxicityThere were no known overdoses of clofarabine. The highest daily dose administered to a human to date (on a mg/m2 basis) has been 70 mg/m2/day × 5 days (2 pediatric ALL patients). The toxicities included in these 2 patients included grade 4 hyperbilirubinemia, grade 2 and 3 vomiting, and grade 3 maculopapular rash.
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+1.0
Blood Brain Barrier+0.9827
Caco-2 permeable-0.7369
P-glycoprotein substrateNon-substrate0.8001
P-glycoprotein inhibitor INon-inhibitor0.9382
P-glycoprotein inhibitor IINon-inhibitor0.8279
Renal organic cation transporterNon-inhibitor0.9144
CYP450 2C9 substrateNon-substrate0.9031
CYP450 2D6 substrateNon-substrate0.8291
CYP450 3A4 substrateNon-substrate0.5681
CYP450 1A2 substrateNon-inhibitor0.817
CYP450 2C9 substrateNon-inhibitor0.8462
CYP450 2D6 substrateNon-inhibitor0.8849
CYP450 2C19 substrateNon-inhibitor0.8391
CYP450 3A4 substrateNon-inhibitor0.8499
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9002
Ames testNon AMES toxic0.7338
CarcinogenicityNon-carcinogens0.7723
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.2651 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9643
hERG inhibition (predictor II)Non-inhibitor0.8304
Pharmacoeconomics
Manufacturers
  • Genzyme corp
Packagers
Dosage forms
FormRouteStrength
Injectionintravenous1 mg/mL
Solutionintravenous1 mg
Prices
Unit descriptionCostUnit
Clolar 20 mg/20 ml vial135.0USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
Canada21027822003-09-162012-05-07
United States56611361998-07-142018-07-14
Properties
StateSolid
Experimental Properties
PropertyValueSource
logP0Not Available
Predicted Properties
PropertyValueSource
Water Solubility4.89 mg/mLALOGPS
logP0.32ALOGPS
logP-0.29ChemAxon
logS-1.8ALOGPS
pKa (Strongest Acidic)12.71ChemAxon
pKa (Strongest Basic)1.3ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area119.31 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity67 m3·mol-1ChemAxon
Polarizability26.06 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 ReferenceNot Available
General Reference
  1. Pession A, Masetti R, Kleinschmidt K, Martoni A: Use of clofarabine for acute childhood leukemia. Biologics. 2010 Jun 24;4:111-8. Pubmed
  2. Harned TM, Gaynon PS: Treating refractory leukemias in childhood, role of clofarabine. Ther Clin Risk Manag. 2008 Apr;4(2):327-36. 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. Larson ML, Venugopal P: Clofarabine: a new treatment option for patients with acute myeloid leukemia. Expert Opin Pharmacother. 2009 Jun;10(8):1353-7. Pubmed
  5. Zhenchuk A, Lotfi K, Juliusson G, Albertioni F: Mechanisms of anti-cancer action and pharmacology of clofarabine. Biochem Pharmacol. 2009 Dec 1;78(11):1351-9. Epub 2009 Jul 1. Pubmed
External Links
ATC CodesL01BB06
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelDownload (281 KB)
MSDSNot Available
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

1. DNA polymerase alpha catalytic subunit

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
DNA polymerase alpha catalytic subunit P09884 Details

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. Pession A, Masetti R, Kleinschmidt K, Martoni A: Use of clofarabine for acute childhood leukemia. Biologics. 2010 Jun 24;4:111-8. Pubmed
  4. Clofarabine. Drugs R D. 2004;5(4):213-7. Pubmed
  5. Musto P, Ferrara F: Clofarabine: in search of combinations for the treatment of patients with high-risk acute myeloid leukemia. Cancer. 2008 Oct 15;113(8):1995-8. Pubmed
  6. Harned TM, Gaynon PS: Treating refractory leukemias in childhood, role of clofarabine. Ther Clin Risk Manag. 2008 Apr;4(2):327-36. Pubmed
  7. Kantarjian HM, Jeha S, Gandhi V, Wess M, Faderl S: Clofarabine: past, present, and future. Leuk Lymphoma. 2007 Oct;48(10):1922-30. Pubmed
  8. 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
  9. Zhenchuk A, Lotfi K, Juliusson G, Albertioni F: Mechanisms of anti-cancer action and pharmacology of clofarabine. Biochem Pharmacol. 2009 Dec 1;78(11):1351-9. Epub 2009 Jul 1. Pubmed

2. Ribonucleoside-diphosphate reductase large subunit

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Ribonucleoside-diphosphate reductase large subunit P23921 Details

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. Pession A, Masetti R, Kleinschmidt K, Martoni A: Use of clofarabine for acute childhood leukemia. Biologics. 2010 Jun 24;4:111-8. Pubmed
  4. Clofarabine. Drugs R D. 2004;5(4):213-7. Pubmed
  5. Musto P, Ferrara F: Clofarabine: in search of combinations for the treatment of patients with high-risk acute myeloid leukemia. Cancer. 2008 Oct 15;113(8):1995-8. Pubmed
  6. Harned TM, Gaynon PS: Treating refractory leukemias in childhood, role of clofarabine. Ther Clin Risk Manag. 2008 Apr;4(2):327-36. Pubmed
  7. Kantarjian HM, Jeha S, Gandhi V, Wess M, Faderl S: Clofarabine: past, present, and future. Leuk Lymphoma. 2007 Oct;48(10):1922-30. Pubmed
  8. 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
  9. Zhenchuk A, Lotfi K, Juliusson G, Albertioni F: Mechanisms of anti-cancer action and pharmacology of clofarabine. Biochem Pharmacol. 2009 Dec 1;78(11):1351-9. Epub 2009 Jul 1. Pubmed

3. DNA

Kind: nucleotide

Organism: Human

Pharmacological action: yes

Actions: other/unknown

Components

Name UniProt ID Details

References:

  1. Pession A, Masetti R, Kleinschmidt K, Martoni A: Use of clofarabine for acute childhood leukemia. Biologics. 2010 Jun 24;4:111-8. Pubmed
  2. Harned TM, Gaynon PS: Treating refractory leukemias in childhood, role of clofarabine. Ther Clin Risk Manag. 2008 Apr;4(2):327-36. Pubmed

Enzymes

1. Deoxycytidine kinase

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Deoxycytidine kinase P27707 Details

References:

  1. Pession A, Masetti R, Kleinschmidt K, Martoni A: Use of clofarabine for acute childhood leukemia. Biologics. 2010 Jun 24;4:111-8. Pubmed
  2. Zhenchuk A, Lotfi K, Juliusson G, Albertioni F: Mechanisms of anti-cancer action and pharmacology of clofarabine. Biochem Pharmacol. 2009 Dec 1;78(11):1351-9. Epub 2009 Jul 1. Pubmed
  3. Kantarjian HM, Jeha S, Gandhi V, Wess M, Faderl S: Clofarabine: past, present, and future. Leuk Lymphoma. 2007 Oct;48(10):1922-30. Pubmed

Transporters

1. ATP-binding cassette sub-family G member 2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
ATP-binding cassette sub-family G member 2 Q9UNQ0 Details

References:

  1. de Wolf C, Jansen R, Yamaguchi H, de Haas M, van de Wetering K, Wijnholds J, Beijnen J, Borst P: Contribution of the drug transporter ABCG2 (breast cancer resistance protein) to resistance against anticancer nucleosides. Mol Cancer Ther. 2008 Sep;7(9):3092-102. Epub 2008 Sep 2. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:11