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Identification
Name Cytarabine
Accession Number DB00987 (APRD00499)
Type small molecule
Groups approved
Description

A pyrimidine nucleoside analog that is used mainly in the treatment of leukemia, especially acute non-lymphoblastic leukemia. Cytarabine is an antimetabolite antineoplastic agent that inhibits the synthesis of DNA. Its actions are specific for the S phase of the cell cycle. It also has antiviral and immunosuppressant properties. (From Martindale, The Extra Pharmacopoeia, 30th ed, p472)
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Ara-C
  • Arabinocytidine
  • Arabinofuranosylcytosine
  • Arabinosylcytosine
  • AraC
  • Aracytidine
  • Aracytin
  • Aracytine
  • beta-Arabinosylcytosine
  • Beta-cytosine arabinoside
  • beta-D-Arabinosylcytosine
  • Citarabina [INN-Spanish]
  • Cytarabin
  • Cytarabina
  • cytarabine liposome injection
  • Cytarabinoside
  • Cytarabinum [INN-Latin]
  • Cytosine 1-beta-D-arabinofuranoside
  • Cytosine arabinofuranoside
  • Cytosine arabinose
  • Cytosine arabinoside
  • Cytosine beta-D-arabinoside
  • Cytosine-1-beta-D-arabinofuranoside
  • Cytosine-beta-arabinoside
  • Cytosine-beta-D-arabinofuranoside
  • Cytosine, beta-D-arabinoside
Brand names
  • Alexan
  • AR3
  • Arabitin
  • Arafcyt
  • Cytarbel
  • Cytosar
  • Cytosar-U
  • Depocyt
  • Depocyt (liposomal)
  • Erpalfa
  • Iretin
  • Spongocytidine
  • Tarabine
  • Udicil
Brand name mixtures Not Available
Categories
  • Antineoplastic Agents
  • Antiviral Agents
  • Antimetabolites
  • Immunosuppressive Agents
  • Antimetabolites, Antineoplastic
CAS number 147-94-4
Weight Average: 243.2166
Monoisotopic: 243.085520541
Chemical Formula C9H13N3O5
InChI Key InChIKey=UHDGCWIWMRVCDJ-CCXZUQQUSA-N
InChI
InChI=1S/C9H13N3O5/c10-5-1-2-12(9(16)11-5)8-7(15)6(14)4(3-13)17-8/h1-2,4,6-8,13-15H,3H2,(H2,10,11,16)/t4-,6-,7+,8-/m1/s1
Plain Text
IUPAC Name
4-amino-1-[(2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2-dihydropyrimidin-2-one
SMILES
NC1=NC(=O)N(C=C1)[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Carbohydrates
Substructures
  • Glycerol and Derivatives
  • Hydroxy Compounds
  • Aliphatic and Aryl Amines
  • Ethers
  • Alcohols and Polyols
  • Pyrimidines and Derivatives
  • Heterocyclic compounds
  • Aromatic compounds
  • Furans
  • Cyanamides
  • Carbohydrates
Pharmacology
Indication For the treatment of acute non-lymphocytic leukemia, acute lymphocytic leukemia and blast phase of chronic myelocytic leukemia.
Pharmacodynamics Cytarabine is an antineoplastic anti-metabolite used in the treatment of several forms of leukemia including acute myelogenous leukemia and meningeal leukemia. Anti-metabolites masquerade as purine or pyrimidine - which become the building blocks of DNA. They prevent these substances becoming incorporated in to DNA during the "S" phase (of the cell cycle), stopping normal development and division. Cytarabine is metabolized intracellularly into its active triphosphate form (cytosine arabinoside triphosphate). This metabolite then damages DNA by multiple mechanisms, including the inhibition of alpha-DNA polymerase, inhibition of DNA repair through an effect on beta-DNA polymerase, and incorporation into DNA. The latter mechanism is probably the most important. Cytotoxicity is highly specific for the S phase of the cell cycle.
Mechanism of action Cytarabine acts through direct DNA damage and incorporation into DNA. Cytarabine is cytotoxic to a wide variety of proliferating mammalian cells in culture. It exhibits cell phase specificity, primarily killing cells undergoing DNA synthesis (S-phase) and under certain conditions blocking the progression of cells from the G1 phase to the S-phase. Although the mechanism of action is not completely understood, it appears that cytarabine acts through the inhibition of DNA polymerase. A limited, but significant, incorporation of cytarabine into both DNA and RNA has also been reported.
Absorption Less than 20% of the orally administered dose is absorbed from the gastrointestinal tract.
Volume of distribution Not Available
Protein binding 13%
Metabolism

Hepatic.
Route of elimination The primary route of elimination of cytarabine is metabolism to the inactive compound ara-U, followed by urinary excretion of ara-U.
Half life 10 minutes
Clearance Not Available
Toxicity Cytarabine syndrome may develop - it is characterized by fever, myalgia, bone pain, occasionally chest pain, maculopapular rash, conjunctivitis, and malaise.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Pacira pharmaceuticals inc
  • App pharmaceuticals llc
  • Bedford laboratories div ben venue laboratories inc
  • Hospira inc
  • Teva parenteral medicines inc
Packagers
Dosage forms
Form Route Strength
Powder, for solution Intrathecal
Solution Intrathecal
Suspension Intrathecal
Prices
Unit description Cost Unit
Depocyt 50 mg/5 ml vial 588.0 USD ml
Cytarabine 2 gm vial 48.0 USD vial
Cytarabine 1 gm vial 24.0 USD vial
Patents
Country Patent Number Approved Expires
United States 5723147 1995-03-03 2015-03-03
United States 5455044 1993-05-14 2013-05-14
Properties
State solid
Melting point 212-213oC
Experimental Properties
Property Value Source
water solubility Freely soluble PhysProp
logP -2.8 PhysProp
Predicted Properties
Property Value Source
water solubility 4.38e+01 g/l ALOGPS
logP -2.18 ALOGPS
logP -2.80 ChemAxon Molconvert
logS -0.74 ALOGPS
pKa 13.93 ChemAxon Molconvert
hydrogen acceptor count 7 ChemAxon Molconvert
hydrogen donor count 4 ChemAxon Molconvert
polar surface area 128.61 ChemAxon Molconvert
rotatable bond count 2 ChemAxon Molconvert
refractivity 54.54 ChemAxon Molconvert
polarizability 22.21 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D00168 Link_out
KEGG Compound C02961 Link_out
PubChem Compound 6253 Link_out
PubChem Substance 46505879 Link_out
ChemSpider 6017 Link_out
ChEBI 28680 Link_out
ChEMBL 28680 Link_out
Therapeutic Targets Database DNC001551 Link_out
HET AR3 Link_out
Drug Product Database 2167883 Link_out
RxList http://www.rxlist.com/cgi/generic3/cytarabine.htm Link_out
Drugs.com http://www.drugs.com/cdi/cytarabine.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Cytarabine Link_out
ATC Codes
  • L01BC01
AHFS Codes
  • 10:00.00
PDB Entries
FDA label show (49.8 KB)
MSDS show (36.8 KB)
Interactions
Drug Interactions Not Available
Food Interactions Not Available
Targets

1. DNA

Pharmacological action: yes
Actions: cross-linking/alkylation

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. Prakasha Gowda AS, Polizzi JM, Eckert KA, Spratt TE: Incorporation of gemcitabine and cytarabine into DNA by DNA polymerase beta and ligase III/XRCC1. Biochemistry. 2010 Jun 15;49(23):4833-40. Pubmed
  2. Foti M, Omichinski JG, Stahl S, Maloney D, West J, Schweitzer BI: Effects of nucleoside analog incorporation on DNA binding to the DNA binding domain of the GATA-1 erythroid transcription factor. FEBS Lett. 1999 Feb 5;444(1):47-53. Pubmed

2. DNA polymerase beta

Pharmacological action: yes
Actions: inhibitor

Repair polymerase. Conducts "gap-filling" DNA synthesis in a stepwise distributive fashion rather than in a processive fashion as for other DNA polymerases. Has a 5'-deoxyribose-5- phosphate lyase (dRP lyase) activity

Organism class: human
UniProt ID: P06746 Link_out
Gene: POLB Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Angeli JP, Ribeiro LR, Bellini MF, Mantovanil: Anti-clastogenic effect of beta-glucan extracted from barley towards chemically induced DNA damage in rodent cells. Hum Exp Toxicol. 2006 Jun;25(6):319-24. Pubmed
  2. Miura S, Izuta S: DNA polymerases as targets of anticancer nucleosides. Curr Drug Targets. 2004 Feb;5(2):191-5. Pubmed
  3. Krynetskaia NF, Phadke MS, Jadhav SH, Krynetskiy EY: Chromatin-associated proteins HMGB1/2 and PDIA3 trigger cellular response to chemotherapy-induced DNA damage. Mol Cancer Ther. 2009 Apr;8(4):864-72. Pubmed
Enzymes

1. Cytidine deaminase

Actions: substrate

This enzyme scavenge exogenous and endogenous cytidine and 2'-deoxycytidine for UMP synthesis

UniProt ID: P32320 Link_out
Gene: CDA
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Ohta T, Hori H, Ogawa M, Miyahara M, Kawasaki H, Taniguchi N, Komada Y: Impact of cytidine deaminase activity on intrinsic resistance to cytarabine in carcinoma cells. Oncol Rep. 2004 Nov;12(5):1115-20. Pubmed
  2. Lamba JK: Genetic factors influencing cytarabine therapy. Pharmacogenomics. 2009 Oct;10(10):1657-74. Pubmed

2. Cytochrome P450 3A4

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

3. Deoxycytidine kinase

Actions: substrate

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

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

References:
  1. Ohta T, Hori H, Ogawa M, Miyahara M, Kawasaki H, Taniguchi N, Komada Y: Impact of cytidine deaminase activity on intrinsic resistance to cytarabine in carcinoma cells. Oncol Rep. 2004 Nov;12(5):1115-20. Pubmed
  2. Lamba JK: Genetic factors influencing cytarabine therapy. Pharmacogenomics. 2009 Oct;10(10):1657-74. Pubmed

4. 5'-nucleotidase

Actions: substrate

Hydrolyzes extracellular nucleotides into membrane permeable nucleosides

UniProt ID: P21589 Link_out
Gene: NT5E Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Lamba JK: Genetic factors influencing cytarabine therapy. Pharmacogenomics. 2009 Oct;10(10):1657-74. Pubmed

5. Deoxycytidylate deaminase

Actions: substrate
UniProt ID: P32321 Link_out

References:
  1. Lamba JK: Genetic factors influencing cytarabine therapy. Pharmacogenomics. 2009 Oct;10(10):1657-74. Pubmed
Transporters

1. Solute carrier family 22 member 2

Actions: substrate

Mediates tubular uptake of organic compounds from circulation. Mediates the influx of agmatine, dopamine, noradrenaline (norepinephrine), serotonin, choline, famotidine, ranitidine, histamin, creatinine, amantadine, memantine, acriflavine, 4-[4-(dimethylamino)-styryl]-N-methylpyridinium ASP, amiloride, metformin, N-1-methylnicotinamide (NMN), tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, cisplatin and oxaliplatin. Cisplatin may develop a nephrotoxic action. Transport of creatinine is inhibited by fluoroquinolones such as DX-619 and LVFX. This transporter is a major determinant of the anticancer activity of oxaliplatin and may contribute to antitumor specificity

UniProt ID: O15244 Link_out
Gene: SLC22A2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Chen R, Nelson JA: Role of organic cation transporters in the renal secretion of nucleosides. Biochem Pharmacol. 2000 Jul 15;60(2):215-9. Pubmed

2. Solute carrier family 22 member 1

Actions: substrate

Translocates a broad array of organic cations with various structures and molecular weights including the model compounds 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA), N-1-methylnicotinamide (NMN), 4-(4-(dimethylamino)styryl)- N-methylpyridinium (ASP), the endogenous compounds choline, guanidine, histamine, epinephrine, adrenaline, noradrenaline and dopamine, and the drugs quinine, and metformin. The transport of organic cations is inhibited by a broad array of compounds like tetramethylammonium (TMA), cocaine, lidocaine, NMDA receptor antagonists, atropine, prazosin, cimetidine, TEA and NMN, guanidine, cimetidine, choline, procainamide, quinine, tetrabutylammonium, and tetrapentylammonium. Translocates organic cations in an electrogenic and pH-independent manner. Translocates organic cations across the plasma membrane in both directions. Transports the polyamines spermine and spermidine. Transports pramipexole across the basolateral membrane of the proximal tubular epithelial cells. The choline transport is activated by MMTS. Regulated by various intracellular signaling pathways including inhibition by protein kinase A activation, and endogenously activation by the calmodulin complex, the calmodulin- dependent kinase II and LCK tyrosine kinase

UniProt ID: O15245 Link_out
Gene: SLC22A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Chen R, Nelson JA: Role of organic cation transporters in the renal secretion of nucleosides. Biochem Pharmacol. 2000 Jul 15;60(2):215-9. Pubmed

3. Multidrug resistance-associated protein 7

Actions: substrate

ATP-dependent transporter probably involved in cellular detoxification through lipophilic anion extrusion

UniProt ID: Q5T3U5 Link_out
Gene: ABCC10 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Hopper-Borge E, Xu X, Shen T, Shi Z, Chen ZS, Kruh GD: Human multidrug resistance protein 7 (ABCC10) is a resistance factor for nucleoside analogues and epothilone B. Cancer Res. 2009 Jan 1;69(1):178-84. Pubmed

4. 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 August 18, 2011 10:43

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.