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Identification
NameAzacitidine
Accession NumberDB00928  (APRD00809)
Typesmall molecule
Groupsapproved, investigational
Description

A pyrimidine nucleoside analogue that inhibits DNA methyltransferase, impairing DNA methylation. It is also an antimetabolite of cytidine, incorporated primarily into RNA. Azacytidine has been used as an antineoplastic agent. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
5 AZCNot AvailableNot Available
AzacitidinaSpanishINN
AzacitidinumLatinINN
AzacytidineNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
LadakamycinNot Available
MylosarNot Available
VidazaNot Available
Brand mixturesNot Available
Categories
CAS number320-67-2
WeightAverage: 244.2047
Monoisotopic: 244.080769514
Chemical FormulaC8H12N4O5
InChI KeyNMUSYJAQQFHJEW-KVTDHHQDSA-N
InChI
InChI=1S/C8H12N4O5/c9-7-10-2-12(8(16)11-7)6-5(15)4(14)3(1-13)17-6/h2-6,13-15H,1H2,(H2,9,11,16)/t3-,4-,5-,6-/m1/s1
IUPAC Name
4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2-dihydro-1,3,5-triazin-2-one
SMILES
NC1=NC(=O)N(C=N1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassOrganooxygen Compounds
ClassCarbohydrates and Carbohydrate Conjugates
SubclassGlycosyl Compounds
Direct parentPyrimidine Nucleosides and Analogues
Alternative parentsPentoses; Triazinones; Aminotriazines; Primary Aromatic Amines; Tetrahydrofurans; Oxolanes; Secondary Alcohols; 1,2-Diols; Ethers; Primary Alcohols; Polyamines
Substituentspentose monosaccharide; amino-1,3,5-triazine; triazinone; triazine; primary aromatic amine; monosaccharide; tetrahydrofuran; oxolane; secondary alcohol; 1,2-diol; ether; polyamine; primary alcohol; alcohol; organonitrogen compound; amine; primary amine
Classification descriptionThis compound belongs to the pyrimidine nucleosides and analogues. These are compounds comprising a pyrimidine base attached to a sugar.
Pharmacology
IndicationFor treatment of patients with the following French-American-British myelodysplastic syndrome subtypes: refractory anemia or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation (now classified as acute myelogenous leukemia with multilineage dysplasia), and chronic myelomonocytic leukemia.
PharmacodynamicsAzacitidine is believed to exert its antineoplastic effects by causing hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in the bone marrow. The concentration of azacitidine required for maximum inhibition of DNA methylation in vitro does not cause major suppression of DNA synthesis. Hypomethylation may restore normal function to genes that are critical for differentiation and proliferation. The cytotoxic effects of azacitidine cause the death of rapidly dividing cells, including cancer cells that are no longer responsive to normal growth control mechanisms. Non-proliferating cells are relatively insensitive to azacitidine. Upon uptake into cells, azacitidine is phosphorylated to 5-azacytidine monophosphate by uridine-cytidine kinase, then to diphosphate by pyrimidine monophosphate kinases and triphosphate by diphosphate kinases. 5-Azacitidine triphosphate is incorporated into RNA, leading to the disruption of nuclear and cytoplasmic RNA metabolism and inhibition of protein synthesis. 5-Azacytidine diphosphate is reduced to 5-aza-deoxycytidine diphosphate by ribonucleotide reductase. The resultant metabolite is phosphorylated to 5-azadeoxycitidine triphosphate by nucleoside diphosphate kinases. 5-azadeoxycitidine triphosphate is then incoporated into DNA, leading to inhibition of DNA synthesis. Azacitidine is most toxic during the S-phase of the cell cycle.
Mechanism of actionAzacitidine (5-azacytidine) is a chemical analogue of the cytosine nucleoside used in DNA and RNA. Azacitidine is thought to induce antineoplastic activity via two mechanisms; inhibition of DNA methyltransferase at low doses, causing hypomethylation of DNA, and direct cytotoxicity in abnormal hematopoietic cells in the bone marrow through its incorporation into DNA and RNA at high doses, resulting in cell death. As azacitidine is a ribonucleoside, it incoporates into RNA to a larger extent than into DNA. The incorporation into RNA leads to the dissembly of polyribosomes, defective methylation and acceptor function of transfer RNA, and inhibition of the production of protein. Its incorporation into DNA leads to a covalent binding with DNA methyltransferases, which prevents DNA synthesis and subsequent cytotoxicity.
AbsorptionAzacitidine is rapidly absorbed after subcutaneous administration. The bioavailability of subcutaneous azacitidine relative to IV azacitidine is approximately 89%, based on area under the curve.
Volume of distribution
  • 76 ± 26 L
Protein bindingNot Available
Metabolism

An in vitro study of azacitidine incubation in human liver fractions indicated that azacitidine may be metabolized by the liver. The potential of azacitidine to inhibit cytochrome P450 (CYP) enzymes is not known.

Route of eliminationFollowing IV administration of radioactive azacitidine to 5 cancer patients, the cumulative urinary excretion was 85% of the radioactive dose. Fecal excretion accounted for <1% of administered radioactivity over three days. Mean excretion of radioactivity in urine following SC administration of 14C-azacitidine was 50%.
Half lifeMean elimination half-life is approximately 4 hours.
Clearance
  • 167 +/- 49 L/h
ToxicityOne case of overdose with azacitidine was reported during clinical trials. A patient experienced diarrhea, nausea, and vomiting after receiving a single IV dose of approximately 290 mg/m2, almost 4 times the recommended starting dose.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9509
Blood Brain Barrier + 0.8753
Caco-2 permeable - 0.8715
P-glycoprotein substrate Non-substrate 0.7879
P-glycoprotein inhibitor I Non-inhibitor 0.9591
P-glycoprotein inhibitor II Non-inhibitor 0.9671
Renal organic cation transporter Non-inhibitor 0.9355
CYP450 2C9 substrate Non-substrate 0.8103
CYP450 2D6 substrate Non-substrate 0.8572
CYP450 3A4 substrate Non-substrate 0.6067
CYP450 1A2 substrate Non-inhibitor 0.9045
CYP450 2C9 substrate Non-inhibitor 0.9436
CYP450 2D6 substrate Non-inhibitor 0.9438
CYP450 2C19 substrate Non-inhibitor 0.9329
CYP450 3A4 substrate Non-inhibitor 0.9617
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9839
Ames test AMES toxic 0.8058
Carcinogenicity Non-carcinogens 0.9182
Biodegradation Not ready biodegradable 0.8432
Rat acute toxicity 1.7991 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9794
hERG inhibition (predictor II) Non-inhibitor 0.8996
Pharmacoeconomics
Manufacturers
  • Celgene corp
Packagers
Dosage forms
FormRouteStrength
Injection, powder, for solutionSubcutaneous
Prices
Unit descriptionCostUnit
Vidaza 100 mg vial588.23USDvial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point229 °CPhysProp
water solubility8.9E+004 mg/LNot Available
logP-3.5Not Available
Predicted Properties
PropertyValueSource
water solubility1.21e+01 g/lALOGPS
logP-2.5ALOGPS
logP-3.1ChemAxon
logS-1.3ALOGPS
pKa (strongest acidic)12.55ChemAxon
pKa (strongest basic)-0.38ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count8ChemAxon
hydrogen donor count4ChemAxon
polar surface area140.97ChemAxon
rotatable bond count2ChemAxon
refractivity52.19ChemAxon
polarizability21.5ChemAxon
number of rings2ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Lorenzo DE FERRA, Maurizio ZENONI, Stefano TURCHETTA, Mauro ANIBALDI, Ettore AMMIRATI, Paolo BRANDI, Giorgio BERARDI, “PROCESS FOR THE SYNTHESIS OF AZACITIDINE AND DECITABINE.” U.S. Patent US20110245485, issued October 06, 2011.

US20110245485
General Reference
  1. Cihak A: Biological effects of 5-azacytidine in eukaryotes. Oncology. 1974;30(5):405-22. Pubmed
  2. Kaminskas E, Farrell AT, Wang YC, Sridhara R, Pazdur R: FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. Oncologist. 2005 Mar;10(3):176-82. Pubmed
  3. Leone G, Voso MT, Teofili L, Lubbert M: Inhibitors of DNA methylation in the treatment of hematological malignancies and MDS. Clin Immunol. 2003 Oct;109(1):89-102. Pubmed
  4. Ghoshal K, Bai S: DNA methyltransferases as targets for cancer therapy. Drugs Today (Barc). 2007 Jun;43(6):395-422. Pubmed
  5. Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R, Stone RM, Nelson D, Powell BL, DeCastro CM, Ellerton J, Larson RA, Schiffer CA, Holland JF: Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. 2002 May 15;20(10):2429-40. Pubmed
  6. Silverman LR: Targeting hypomethylation of DNA to achieve cellular differentiation in myelodysplastic syndromes (MDS). Oncologist. 2001;6 Suppl 5:8-14. Pubmed
  7. Issa JP, Kantarjian H: Azacitidine. Nat Rev Drug Discov. 2005 May;Suppl:S6-7. Pubmed
  8. O’Dwyer K, Maslak P: Azacitidine and the beginnings of therapeutic epigenetic modulation. Expert Opin Pharmacother. 2008 Aug;9(11):1981-6. Pubmed
  9. Siddiqui MA, Scott LJ: Azacitidine: in myelodysplastic syndromes. Drugs. 2005;65(13):1781-9; discussion 1790-1. Pubmed
  10. Abdulhaq H, Rossetti JM: The role of azacitidine in the treatment of myelodysplastic syndromes. Expert Opin Investig Drugs. 2007 Dec;16(12):1967-75. Pubmed
  11. Keating GM: Azacitidine: a review of its use in higher-risk myelodysplastic syndromes/acute myeloid leukaemia. Drugs. 2009;69(17):2501-18. doi: 10.2165/11202840-000000000-00000. Pubmed
  12. Sullivan M, Hahn K, Kolesar JM: Azacitidine: a novel agent for myelodysplastic syndromes. Am J Health Syst Pharm. 2005 Aug 1;62(15):1567-73. Pubmed
  13. Dapp MJ, Clouser CL, Patterson S, Mansky LM: 5-Azacytidine can induce lethal mutagenesis in human immunodeficiency virus type 1. J Virol. 2009 Nov;83(22):11950-8. Epub 2009 Sep 2. Pubmed
External Links
ResourceLink
KEGG DrugD03021
KEGG CompoundC11262
PubChem Compound9444
PubChem Substance46509032
ChemSpider9072
ChEBI2038
ChEMBLCHEMBL1489
Therapeutic Targets DatabaseDAP000640
PharmGKBPA451996
RxListhttp://www.rxlist.com/cgi/generic3/vidaza.htm
Drugs.comhttp://www.drugs.com/cdi/azacitidine.html
WikipediaAzacitidine
ATC CodesNot Available
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelshow(194 KB)
MSDSshow(68.8 KB)
Interactions
Drug Interactions
Drug
TrastuzumabTrastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
Food InteractionsNot Available

Targets

1. DNA (cytosine-5)-methyltransferase 1

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
DNA (cytosine-5)-methyltransferase 1 P26358 Details

References:

  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Kaminskas E, Farrell AT, Wang YC, Sridhara R, Pazdur R: FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. Oncologist. 2005 Mar;10(3):176-82. Pubmed
  3. Cataldo VD, Cortes J, Quintas-Cardama A: Azacitidine for the treatment of myelodysplastic syndrome. Expert Rev Anticancer Ther. 2009 Jul;9(7):875-84. Pubmed
  4. Leone G, Voso MT, Teofili L, Lubbert M: Inhibitors of DNA methylation in the treatment of hematological malignancies and MDS. Clin Immunol. 2003 Oct;109(1):89-102. Pubmed
  5. Ghoshal K, Bai S: DNA methyltransferases as targets for cancer therapy. Drugs Today (Barc). 2007 Jun;43(6):395-422. Pubmed
  6. Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R, Stone RM, Nelson D, Powell BL, DeCastro CM, Ellerton J, Larson RA, Schiffer CA, Holland JF: Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. 2002 May 15;20(10):2429-40. Pubmed
  7. Fenaux P: Inhibitors of DNA methylation: beyond myelodysplastic syndromes. Nat Clin Pract Oncol. 2005 Dec;2 Suppl 1:S36-44. Pubmed
  8. Silverman LR: Targeting hypomethylation of DNA to achieve cellular differentiation in myelodysplastic syndromes (MDS). Oncologist. 2001;6 Suppl 5:8-14. Pubmed
  9. O’Dwyer K, Maslak P: Azacitidine and the beginnings of therapeutic epigenetic modulation. Expert Opin Pharmacother. 2008 Aug;9(11):1981-6. Pubmed
  10. Hollenbach PW, Nguyen AN, Brady H, Williams M, Ning Y, Richard N, Krushel L, Aukerman SL, Heise C, MacBeth KJ: A comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines. PLoS One. 2010 Feb 2;5(2):e9001. Pubmed
  11. Glover AB, Leyland-Jones B: Biochemistry of azacitidine: a review. Cancer Treat Rep. 1987 Oct;71(10):959-64. Pubmed

2. RNA

Kind: nucleotide

Organism: Human

Pharmacological action: yes

Actions: other

Components

Name UniProt ID Details

References:

  1. Muller A, Florek M: 5-Azacytidine/Azacitidine. Recent Results Cancer Res. 2010;184:159-70. Pubmed
  2. Kaminskas E, Farrell AT, Wang YC, Sridhara R, Pazdur R: FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. Oncologist. 2005 Mar;10(3):176-82. Pubmed
  3. Hollenbach PW, Nguyen AN, Brady H, Williams M, Ning Y, Richard N, Krushel L, Aukerman SL, Heise C, MacBeth KJ: A comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines. PLoS One. 2010 Feb 2;5(2):e9001. Pubmed
  4. Glover AB, Leyland-Jones B: Biochemistry of azacitidine: a review. Cancer Treat Rep. 1987 Oct;71(10):959-64. Pubmed
  5. Cihak A, Vesely J, Skoda J: Azapyrimidine nucleosides: metabolism and inhibitory mechanisms. Adv Enzyme Regul. 1985;24:335-54. Pubmed
  6. Dapp MJ, Clouser CL, Patterson S, Mansky LM: 5-Azacytidine can induce lethal mutagenesis in human immunodeficiency virus type 1. J Virol. 2009 Nov;83(22):11950-8. Epub 2009 Sep 2. Pubmed

3. DNA

Kind: nucleotide

Organism: Human

Pharmacological action: yes

Actions: other

Components

Name UniProt ID 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. Allen A: Epigenetic alterations and cancer: New targets for therapy. IDrugs. 2007 Oct;10(10):709-12. Pubmed
  4. Kaminskas E, Farrell AT, Wang YC, Sridhara R, Pazdur R: FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. Oncologist. 2005 Mar;10(3):176-82. Pubmed
  5. O’Dwyer K, Maslak P: Azacitidine and the beginnings of therapeutic epigenetic modulation. Expert Opin Pharmacother. 2008 Aug;9(11):1981-6. Pubmed
  6. Muller A, Florek M: 5-Azacytidine/Azacitidine. Recent Results Cancer Res. 2010;184:159-70. Pubmed
  7. Hollenbach PW, Nguyen AN, Brady H, Williams M, Ning Y, Richard N, Krushel L, Aukerman SL, Heise C, MacBeth KJ: A comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines. PLoS One. 2010 Feb 2;5(2):e9001. Pubmed
  8. Glover AB, Leyland-Jones B: Biochemistry of azacitidine: a review. Cancer Treat Rep. 1987 Oct;71(10):959-64. Pubmed
  9. Cihak A, Vesely J, Skoda J: Azapyrimidine nucleosides: metabolism and inhibitory mechanisms. Adv Enzyme Regul. 1985;24:335-54. Pubmed
  10. Dapp MJ, Clouser CL, Patterson S, Mansky LM: 5-Azacytidine can induce lethal mutagenesis in human immunodeficiency virus type 1. J Virol. 2009 Nov;83(22):11950-8. Epub 2009 Sep 2. Pubmed

Enzymes

1. Cytidine deaminase

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytidine deaminase P32320 Details

References:

  1. Garcia-Manero G, Stoltz ML, Ward MR, Kantarjian H, Sharma S: A pilot pharmacokinetic study of oral azacitidine. Leukemia. 2008 Sep;22(9):1680-4. Epub 2008 Jun 12. Pubmed

Comments
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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:12