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IdentificationPharmacologyInteractionsReferencesTrialsEconomicsPropertiesSpectraTaxonomyIdentification
- Name
- Decitabine
- Accession Number
- DB01262
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Description
Decitabine is indicated for treatment of patients with myelodysplastic syndrome (MDS). It is a chemical analogue of cytidine, a nucleoside present in DNA and RNA. Cells in the presence of Decitabine incorporate it into DNA during replication and RNA during transcription. The incorporation of Decitabine into DNA or RNA inhibits methyltransferase thereby causing demethylation in that sequence. This adversely affects the way that cell regulatory proteins are able to bind to the DNA/RNA substrate.
- Structure
Structure for Decitabine (DB01262)
- Synonyms
- 4-amino-1-(2-Deoxy-beta-D-erythro-pentofuranosyl)-S-triazin-2(1H)-one
- 5-aza-2'-deoxycytidine
- 5-Azadeoxycytidine
- Azadc
- Decitabina
- Decitabine
- Dezocitidine
- External IDs
- NSC-127716
- Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Dacogen Injection, powder, for solution 50 mg Intravenous Janssen Cilag International Nv 2012-09-20 Not applicable EU 
Dacogen Injection, powder, lyophilized, for solution 50 mg/20mL Intravenous Otsuka Pharmaceutical Co., Ltd. 1996-05-03 Not applicable US 
Dacogen Injection, powder, lyophilized, for solution 50 mg/20mL Intravenous Eisai Limited 1996-05-03 2018-12-31 US Decitabine Kit 50 mg/10mL Sun Pharmaceutical Industries, Inc. 2014-01-24 Not applicable US - Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Decitabine Injection, powder, lyophilized, for solution 50 mg/50mL Intravenous Sandoz 2014-08-28 Not applicable US Decitabine Injection, powder, lyophilized, for solution 50 mg/20mL Intravenous Sagent Pharmaceuticals 2018-08-15 Not applicable US Decitabine Injection, powder, lyophilized, for solution 50 mg/10mL Intravenous Dr.Reddy's Laboratories Inc. 2013-07-11 Not applicable US Decitabine Injection, powder, lyophilized, for solution 50 mg/20mL Intravenous Accord Healthcare Inc. 2017-03-08 Not applicable US Decitabine Injection 50 mg/10mL Intravenous Cipla USA Inc. 2017-11-16 Not applicable US Decitabine Injection, powder, lyophilized, for solution 50 mg/10mL Intravenous Dr Reddy's Laboratories 2013-07-11 Not applicable US Decitabine Injection, powder, lyophilized, for solution 50 mg/20mL Intravenous Mylan Institutional LLC 2018-10-10 Not applicable US Decitabine Injection, powder, lyophilized, for solution 50 mg/20mL Intravenous North Star Rx Llc 2017-11-20 Not applicable US Decitabine Injection, powder, lyophilized, for solution 50 mg/10mL Intravenous Dr.Reddy's Laboratories Inc. 2014-12-05 Not applicable US Decitabine Injection, powder, lyophilized, for solution 50 mg/20mL Intravenous Chemi Pharma Llc 2018-10-31 Not applicable US - Categories
- Antimetabolites
- Antimetabolites, Antineoplastic
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- Aza Compounds
- Carbohydrates
- Cytidine
- DNA Modification Methylases, antagonists & inhibitors
- Enzyme Inhibitors
- Glycosides
- Immunosuppressive Agents
- Myelodysplastic Syndromes
- Myelosuppressive Agents
- Noxae
- Nucleic Acid Synthesis Inhibitors
- Nucleic Acids, Nucleotides, and Nucleosides
- Nucleoside Metabolic Inhibitor
- Nucleosides
- Pyrimidine Analogues
- Pyrimidine Nucleosides
- Pyrimidines
- Ribonucleosides
- Teratogens
- Toxic Actions
- UNII
- 776B62CQ27
- CAS number
- 2353-33-5
- Weight
- Average: 228.2053
Monoisotopic: 228.085854892 - Chemical Formula
- C8H12N4O4
- InChI Key
- XAUDJQYHKZQPEU-KVQBGUIXSA-N
- InChI
- InChI=1S/C8H12N4O4/c9-7-10-3-12(8(15)11-7)6-1-4(14)5(2-13)16-6/h3-6,13-14H,1-2H2,(H2,9,11,15)/t4-,5+,6+/m0/s1
- IUPAC Name
- 4-amino-1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2-dihydro-1,3,5-triazin-2-one
- SMILES
- NC1=NC(=O)N(C=N1)[C@H]1C[C@H](O)[C@@H](CO)O1
Pharmacology
- Indication
For treatment of patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups (scores ≥0.5).
- Associated Conditions
- Pharmacodynamics
Decitabine is an analogue of the natural nucleoside 2’-deoxycytidine. It functions in the same way as 5-Azacytidine. The antineoplastic activity of this drug is dependent on its intracellular conversion to its 5'-triphosphate metabolite.
- Mechanism of action
Decitabine is believed to exert its antineoplastic effects following its conversion to decitabine triphosphate, where the drug directly incorporates into DNA and inhibits DNA methyltransferase, the enzyme that is responsible for methylating newly synthesized DNA in mammalian cells. This results in hypomethylation of DNA and cellular differentiation or apoptosis. Decitabine inhibits DNA methylation in vitro, which is achieved at concentrations that do not cause major suppression of DNA synthesis. Decitabine-induced hypomethylation in neoplastic cells may restore normal function to genes that are critical for the control of cellular differentiation and proliferation. In rapidly dividing cells, the cytotoxicity of decitabine may also be attributed to the formation of covalent adducts between DNA methyltransferase and decitabine that has been incorporated into DNA. Non-proliferating cells are relatively insensitive to decitabine. Decitabine is cell cycle specific and acts peripherally in the S phase of the cell cycle. It does not inhibit the progression of cells from the G1 to S phase.
Target Actions Organism ADNA other/unknownHuman ADNA (cytosine-5)-methyltransferase 1 inhibitorHuman - Absorption
- Not Available
- Volume of distribution
- Not Available
- Protein binding
Plasma protein binding of decitabine is negligible (<1%).
- Metabolism
The exact route of elimination and metabolic fate of decitabine is not known in humans. One of the pathways of elimination of decitabine appears to be deamination by cytidine deaminase found principally in the liver but also in granulocytes, intestinal epithelium and whole blood.
- Route of elimination
- Not Available
- Half life
The terminal phase elimination half-life is 0.51 ± 0.31 hours.
- Clearance
- 125 L/h/m2 [Patients receiving 15 mg/m2 3-hr infusion every 8 hours for 3 days]
- 210 L/h/m2 [20 mg/m2 1-hr infusion daily for 5 days]
- Toxicity
There is no known antidote for overdosage with decitabine. Higher doses are associated with increased myelosuppression including prolonged neutropenia and thrombocytopenia.
- Affected organisms
- Humans and other mammals
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
Drug Interaction (R)-warfarin The risk or severity of bleeding can be increased when (R)-warfarin is combined with Decitabine. (S)-Warfarin The risk or severity of bleeding can be increased when (S)-Warfarin is combined with Decitabine. 2-Methoxyethanol The risk or severity of adverse effects can be increased when Decitabine is combined with 2-Methoxyethanol. 4-hydroxycoumarin The risk or severity of bleeding can be increased when 4-hydroxycoumarin is combined with Decitabine. 9-(N-methyl-L-isoleucine)-cyclosporin A The risk or severity of adverse effects can be increased when Decitabine is combined with 9-(N-methyl-L-isoleucine)-cyclosporin A. Abatacept The risk or severity of adverse effects can be increased when Decitabine is combined with Abatacept. Abciximab The risk or severity of bleeding can be increased when Abciximab is combined with Decitabine. Abetimus The risk or severity of adverse effects can be increased when Decitabine is combined with Abetimus. Acenocoumarol The risk or severity of bleeding can be increased when Acenocoumarol is combined with Decitabine. Acetylsalicylic acid The risk or severity of bleeding can be increased when Acetylsalicylic acid is combined with Decitabine. - Food Interactions
- Not Available
References
- Synthesis Reference
Julian Paul Henschke, Xiaoheng Zhang, Jianbo Yu, Kun Hu, Lijun Mei, "Synthesis of Decitabine." U.S. Patent US20100087637, issued April 08, 2010.
US20100087637- General References
- Appleton K, Mackay HJ, Judson I, Plumb JA, McCormick C, Strathdee G, Lee C, Barrett S, Reade S, Jadayel D, Tang A, Bellenger K, Mackay L, Setanoians A, Schatzlein A, Twelves C, Kaye SB, Brown R: Phase I and pharmacodynamic trial of the DNA methyltransferase inhibitor decitabine and carboplatin in solid tumors. J Clin Oncol. 2007 Oct 10;25(29):4603-9. [PubMed:17925555]
- Wijermans PW, Ruter B, Baer MR, Slack JL, Saba HI, Lubbert M: Efficacy of decitabine in the treatment of patients with chronic myelomonocytic leukemia (CMML). Leuk Res. 2008 Apr;32(4):587-91. Epub 2007 Sep 18. [PubMed:17881052]
- Daskalakis M, Blagitko-Dorfs N, Hackanson B: Decitabine. Recent Results Cancer Res. 2010;184:131-57. doi: 10.1007/978-3-642-01222-8_10. [PubMed:20072836]
- Saba HI, Wijermans PW: Decitabine in myelodysplastic syndromes. Semin Hematol. 2005 Jul;42(3 Suppl 2):S23-31. [PubMed:16015501]
- Jabbour E, Issa JP, Garcia-Manero G, Kantarjian H: Evolution of decitabine development: accomplishments, ongoing investigations, and future strategies. Cancer. 2008 Jun;112(11):2341-51. doi: 10.1002/cncr.23463. [PubMed:18398832]
- Stresemann C, Lyko F: Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int J Cancer. 2008 Jul 1;123(1):8-13. doi: 10.1002/ijc.23607. [PubMed:18425818]
- Oki Y, Aoki E, Issa JP: Decitabine--bedside to bench. Crit Rev Oncol Hematol. 2007 Feb;61(2):140-52. Epub 2006 Oct 4. [PubMed:17023173]
- External Links
- Human Metabolome Database
- HMDB0015391
- KEGG Drug
- D03665
- PubChem Compound
- 451668
- PubChem Substance
- 46505657
- ChemSpider
- 397844
- BindingDB
- 96274
- ChEBI
- 50131
- ChEMBL
- CHEMBL1201129
- Therapeutic Targets Database
- DAP000641
- PharmGKB
- PA164749631
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Decitabine
- ATC Codes
- L01BC08 — Decitabine
- FDA label
- Download (100 KB)
Clinical Trials
- Clinical Trials
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Eisai Inc.
- MGI Pharma
- Pharmachemie BV
- Dosage forms
Form Route Strength Injection, powder, for solution Intravenous 50 mg Injection, powder, lyophilized, for solution Intravenous 50 mg/20mL Injection Intravenous 50 mg/10mL Injection, powder, lyophilized, for solution Intravenous 50 mg/10mL Injection, powder, lyophilized, for solution Intravenous 50 mg/50mL Kit 50 mg/10mL - Prices
Unit description Cost Unit Dacogen 50 mg vial 1706.4USD vial DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility Sparingly soluble Not Available - Predicted Properties
Property Value Source Water Solubility 5.5 mg/mL ALOGPS logP -2 ALOGPS logP -2.2 ChemAxon logS -1.6 ALOGPS pKa (Strongest Acidic) 13.89 ChemAxon pKa (Strongest Basic) -0.25 ChemAxon Physiological Charge 0 ChemAxon Hydrogen Acceptor Count 7 ChemAxon Hydrogen Donor Count 3 ChemAxon Polar Surface Area 120.74 Å2 ChemAxon Rotatable Bond Count 2 ChemAxon Refractivity 50.68 m3·mol-1 ChemAxon Polarizability 21.15 Å3 ChemAxon Number of Rings 2 ChemAxon Bioavailability 1 ChemAxon Rule of Five Yes ChemAxon Ghose Filter No ChemAxon Veber's Rule No ChemAxon MDDR-like Rule No ChemAxon - Predicted ADMET features
Property Value Probability Human Intestinal Absorption + 0.9862 Blood Brain Barrier + 0.8787 Caco-2 permeable - 0.8362 P-glycoprotein substrate Non-substrate 0.7192 P-glycoprotein inhibitor I Non-inhibitor 0.9216 P-glycoprotein inhibitor II Non-inhibitor 0.953 Renal organic cation transporter Non-inhibitor 0.8791 CYP450 2C9 substrate Non-substrate 0.8359 CYP450 2D6 substrate Non-substrate 0.8511 CYP450 3A4 substrate Non-substrate 0.5356 CYP450 1A2 substrate Non-inhibitor 0.9276 CYP450 2C9 inhibitor Non-inhibitor 0.9265 CYP450 2D6 inhibitor Non-inhibitor 0.9446 CYP450 2C19 inhibitor Non-inhibitor 0.9379 CYP450 3A4 inhibitor Non-inhibitor 0.9635 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9629 Ames test Non AMES toxic 0.588 Carcinogenicity Non-carcinogens 0.8109 Biodegradation Not ready biodegradable 0.8957 Rat acute toxicity 1.9436 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9654 hERG inhibition (predictor II) Non-inhibitor 0.8972
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted GC-MS Spectrum - GC-MS Predicted GC-MS Not Available Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not Available
Taxonomy
- Description
- This compound belongs to the class of organic compounds known as triazinones. These are compounds containing a triazine ring which bears a ketone group a carbon atom.
- Kingdom
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Class
- Triazines
- Sub Class
- Triazinones
- Direct Parent
- Triazinones
- Alternative Parents
- Aminotriazines / 1,3,5-triazines / Tetrahydrofurans / Heteroaromatic compounds / Secondary alcohols / Oxacyclic compounds / Azacyclic compounds / Primary amines / Primary alcohols / Organopnictogen compounds show 2 more
- Substituents
- Amino-1,3,5-triazine / Aminotriazine / Triazinone / 1,3,5-triazine / Tetrahydrofuran / Heteroaromatic compound / Secondary alcohol / Oxacycle / Azacycle / Organic oxide show 11 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- 2'-deoxyribonucleoside (CHEBI:50131)
Targets
1. DNA
Yes
Other/unknown
- 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
- 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]
- 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]
- Appleton K, Mackay HJ, Judson I, Plumb JA, McCormick C, Strathdee G, Lee C, Barrett S, Reade S, Jadayel D, Tang A, Bellenger K, Mackay L, Setanoians A, Schatzlein A, Twelves C, Kaye SB, Brown R: Phase I and pharmacodynamic trial of the DNA methyltransferase inhibitor decitabine and carboplatin in solid tumors. J Clin Oncol. 2007 Oct 10;25(29):4603-9. [PubMed:17925555]
- Atallah E, Kantarjian H, Garcia-Manero G: The role of decitabine in the treatment of myelodysplastic syndromes. Expert Opin Pharmacother. 2007 Jan;8(1):65-73. [PubMed:17163808]
- Jabbour E, Issa JP, Garcia-Manero G, Kantarjian H: Evolution of decitabine development: accomplishments, ongoing investigations, and future strategies. Cancer. 2008 Jun;112(11):2341-51. doi: 10.1002/cncr.23463. [PubMed:18398832]
- Stresemann C, Lyko F: Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int J Cancer. 2008 Jul 1;123(1):8-13. doi: 10.1002/ijc.23607. [PubMed:18425818]
- Oki Y, Aoki E, Issa JP: Decitabine--bedside to bench. Crit Rev Oncol Hematol. 2007 Feb;61(2):140-52. Epub 2006 Oct 4. [PubMed:17023173]
- Kind
- Protein
- Organism
- Human
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Zinc ion binding
- Specific Function
- Methylates CpG residues. Preferentially methylates hemimethylated DNA. Associates with DNA replication sites in S phase maintaining the methylation pattern in the newly synthesized strand, that is ...
- Gene Name
- DNMT1
- Uniprot ID
- P26358
- Uniprot Name
- DNA (cytosine-5)-methyltransferase 1
- Molecular Weight
- 183163.635 Da
References
- Ando T, Nishimura M, Oka Y: Decitabine (5-Aza-2'-deoxycytidine) decreased DNA methylation and expression of MDR-1 gene in K562/ADM cells. Leukemia. 2000 Nov;14(11):1915-20. [PubMed:11069027]
- Karpf AR, Moore BC, Ririe TO, Jones DA: Activation of the p53 DNA damage response pathway after inhibition of DNA methyltransferase by 5-aza-2'-deoxycytidine. Mol Pharmacol. 2001 Apr;59(4):751-7. [PubMed:11259619]
- Csankovszki G, Nagy A, Jaenisch R: Synergism of Xist RNA, DNA methylation, and histone hypoacetylation in maintaining X chromosome inactivation. J Cell Biol. 2001 May 14;153(4):773-84. [PubMed:11352938]
- Takebayashi S, Nakao M, Fujita N, Sado T, Tanaka M, Taguchi H, Okumura K: 5-Aza-2'-deoxycytidine induces histone hyperacetylation of mouse centromeric heterochromatin by a mechanism independent of DNA demethylation. Biochem Biophys Res Commun. 2001 Nov 9;288(4):921-6. [PubMed:11688997]
- Saunthararajah Y, Hillery CA, Lavelle D, Molokie R, Dorn L, Bressler L, Gavazova S, Chen YH, Hoffman R, DeSimone J: Effects of 5-aza-2'-deoxycytidine on fetal hemoglobin levels, red cell adhesion, and hematopoietic differentiation in patients with sickle cell disease. Blood. 2003 Dec 1;102(12):3865-70. Epub 2003 Aug 7. [PubMed:12907443]
- Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
- Daskalakis M, Blagitko-Dorfs N, Hackanson B: Decitabine. Recent Results Cancer Res. 2010;184:131-57. doi: 10.1007/978-3-642-01222-8_10. [PubMed:20072836]
- Saba HI, Wijermans PW: Decitabine in myelodysplastic syndromes. Semin Hematol. 2005 Jul;42(3 Suppl 2):S23-31. [PubMed:16015501]
- Jabbour E, Issa JP, Garcia-Manero G, Kantarjian H: Evolution of decitabine development: accomplishments, ongoing investigations, and future strategies. Cancer. 2008 Jun;112(11):2341-51. doi: 10.1002/cncr.23463. [PubMed:18398832]
- Stresemann C, Lyko F: Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int J Cancer. 2008 Jul 1;123(1):8-13. doi: 10.1002/ijc.23607. [PubMed:18425818]
- Oki Y, Aoki E, Issa JP: Decitabine--bedside to bench. Crit Rev Oncol Hematol. 2007 Feb;61(2):140-52. Epub 2006 Oct 4. [PubMed:17023173]
Enzymes
- Kind
- Protein
- Organism
- Human
- Pharmacological action
- Unknown
- 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
- Schwarzenberg J, Radu CG, Benz M, Fueger B, Tran AQ, Phelps ME, Witte ON, Satyamurthy N, Czernin J, Schiepers C: Human biodistribution and radiation dosimetry of novel PET probes targeting the deoxyribonucleoside salvage pathway. Eur J Nucl Med Mol Imaging. 2011 Apr;38(4):711-21. doi: 10.1007/s00259-010-1666-z. Epub 2010 Dec 3. [PubMed:21127859]
Drug created on May 16, 2007 11:38 / Updated on November 05, 2018 17:48