Details of the Drug

General Information of Drug (ID: DMTA5OE)

• Drug Name: Azacitidine
• Synonyms: Azacitidina; Azacitidinum; Azacytidine; Ladakamycin; Mylosar; Vidaza; Mylo sar; Pharmion Brand of Azacitidine;A 2385; Antibiotic U 18496; U 18496; Wr 183027; Azacitidina [INN-Spanish]; Azacitidine [USAN:INN]; Azacitidinum [INN-Latin]; NS-17; Pyrimidine antimetabolite: inhibits nucleic acid replication; U-18496; Vidaz (TN); Vidaza (TN); WR-183027; Azacitidine (JAN/USAN/INN); S-Triazin-2(1H)-one, 4-amino-1-beta-D-ribofuranosyl-(8CI); 2-(beta-D-Ribofuranosyl)-4-amino-1,3,5-triazin-2-one; 4-Amino-1-(beta-D-ribofuranosyl)-1,3,5-triazin-2(1H)-one; 4-Amino-1-beta-D-ribofuranosyl-1,3,5-traizin-2(1H)-one; 4-Amino-1-beta-D-ribofuranosyl-1,3,5-triazine-2(1H)-one; 4-Amino-1-beta-D-ribofuranosyl-s-triazin-2(1H)-one; 4-Amino-1-beta-d-ribofuranosyl-1,3,5-triazin-2(1H)-one; 4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,3,5-triaz; 4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,3,5-triazin-2-one; 4-amino-1-beta-L-ribofuranosyl-1,3,5-triazin-2(1H)-one; 5 AZC; 5 Azacytidine; 5-AC; 5-AZAC; 5-AZCR; 5-aza-CR; 5-azacitidine; 5-azacytidine; 5-azacytidine, Mylosar, Ladakamycin, Vidaza, Azacitidine; 5AzaC

Indication

Disease Entry	ICD 11	Status	REF
Acute myelogenous leukaemia	2A41	Approved	[1]
Chronic myelomonocytic leukemia	N.A.	Approved	[1]
Leukemia	N.A.	Approved	[1]
Myelodysplastic syndrome	2A37	Approved	[2]
Myeloproliferative neoplasm	2A20	Approved	[1]
Plasma cell myeloma	2A83.1	Approved	[1]

• Therapeutic Class: Anticancer Agents
• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 1:
  Molecular Weight (mw); 244.2
  Logarithm of the Partition Coefficient (xlogp); -2.2
  Rotatable Bond Count (rotbonds); 2
  Hydrogen Bond Donor Count (hbonddonor); 4
  Hydrogen Bond Acceptor Count (hbondacc); 5
• ADMET Property:
  BDDCS Class: Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 3: high solubility and low permeability [3]
  Clearance: The clearance of drug is 167 +/- 49 L/h []
  Elimination: 62% of drug is excreted from urine in the unchanged form [3]
  Half-life: The concentration or amount of drug in body reduced by one-half in 4 hours [4]
  Metabolism: The drug is metabolized via the liver []
  MRTD: The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 177.10271 micromolar/kg/day [5]
  Vd: The volume of distribution (Vd) of drug is 76 +/- 26 L []
  Water Solubility: The ability of drug to dissolve in water is measured as 89 mg/mL [3]
• Chemical Identifiers:
  Formula: C8H12N4O5
  IUPAC Name: 4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,3,5-triazin-2-one
  Canonical SMILES: C1=NC(=NC(=O)N1[C@H]2[C@@H]([C@@H]([C@H](O2)CO)O)O)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
  InChIKey: NMUSYJAQQFHJEW-KVTDHHQDSA-N
• Cross-matching ID:
  PubChem CID: 9444
  ChEBI ID: CHEBI:2038
  CAS Number: 320-67-2
  DrugBank ID: DB00928
  TTD ID: D09FAZ
  VARIDT ID: DR00983
  INTEDE ID: DR0163
• Repurposed Drugs (RPD): Click to Jump to the Detailed RPD Information of This Drug

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
DNA [cytosine-5]-methyltransferase (DNMT)	TTHVCUP	NOUNIPROTAC	Inhibitor	[6]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytidine aminohydrolase (CDA)	DEKEDRC	CDD_HUMAN	Substrate	[7]
Cytidine deaminase (cdd)	DEYILK4	E0TLJ6_MYCHH	Substrate	[8]

Drug Off-Target (DOT)

DOT Name	DOT ID	UniProt ID	Interaction	REF
1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 (PLCB1)	OT9HYT7A	PLCB1_HUMAN	Gene/Protein Processing	[9]
15-hydroxyprostaglandin dehydrogenase (HPGD)	OTYZI6JB	PGDH_HUMAN	Post-Translational Modifications	[10]
5'-nucleotidase (NT5E)	OT7J5LT6	5NTD_HUMAN	Gene/Protein Processing	[11]
A disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1)	OTTLJH8W	ATS1_HUMAN	Gene/Protein Processing	[11]
Acyl-CoA 6-desaturase (FADS2)	OTUX531P	FADS2_HUMAN	Gene/Protein Processing	[11]
Adenylate kinase isoenzyme 5 (AK5)	OTTGXLOT	KAD5_HUMAN	Gene/Protein Processing	[11]
Afadin- and alpha-actinin-binding protein (SSX2IP)	OTEIZ7N1	ADIP_HUMAN	Gene/Protein Processing	[11]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Gene/Protein Processing	[12]
Alpha-2,8-sialyltransferase 8B (ST8SIA2)	OTRBBBD8	SIA8B_HUMAN	Gene/Protein Processing	[11]
Alpha-fetoprotein (AFP)	OT9GG3ZI	FETA_HUMAN	Gene/Protein Processing	[12]

Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Disease Different from Azacitidine (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Roflumilast	DMPGHY8	Moderate	Additive immunosuppressive effects by the combination of Azacitidine and Roflumilast.	Asthma [CA23]	[13]
Teriflunomide	DMQ2FKJ	Major	Additive myelosuppressive effects by the combination of Azacitidine and Teriflunomide.	Hyper-lipoproteinaemia [5C80]	[14]
Denosumab	DMNI0KO	Moderate	Additive myelosuppressive effects by the combination of Azacitidine and Denosumab.	Low bone mass disorder [FB83]	[15]
Thalidomide	DM70BU5	Major	Additive thrombogenic effects by the combination of Azacitidine and Thalidomide.	Multiple myeloma [2A83]	[16]
Tecfidera	DM2OVDT	Moderate	Additive immunosuppressive effects by the combination of Azacitidine and Tecfidera.	Multiple sclerosis [8A40]	[17]
Siponimod	DM2R86O	Major	Additive immunosuppressive effects by the combination of Azacitidine and Siponimod.	Multiple sclerosis [8A40]	[18]
Fingolimod	DM5JVAN	Major	Additive immunosuppressive effects by the combination of Azacitidine and Fingolimod.	Multiple sclerosis [8A40]	[19]
Ocrelizumab	DMEZ2KH	Moderate	Additive immunosuppressive effects by the combination of Azacitidine and Ocrelizumab.	Multiple sclerosis [8A40]	[20]
Ozanimod	DMT6AM2	Major	Additive immunosuppressive effects by the combination of Azacitidine and Ozanimod.	Multiple sclerosis [8A40]	[13]
Omacetaxine mepesuccinate	DMPU2WX	Moderate	Additive myelosuppressive effects by the combination of Azacitidine and Omacetaxine mepesuccinate.	Myeloproliferative neoplasm [2A20]	[21]
Canakinumab	DM8HLO5	Moderate	Additive immunosuppressive effects by the combination of Azacitidine and Canakinumab.	Rheumatoid arthritis [FA20]	[22]
Rilonacept	DMGLUQS	Moderate	Additive immunosuppressive effects by the combination of Azacitidine and Rilonacept.	Rheumatoid arthritis [FA20]	[22]
Golimumab	DMHZV7X	Major	Additive immunosuppressive effects by the combination of Azacitidine and Golimumab.	Rheumatoid arthritis [FA20]	[23]
Leflunomide	DMR8ONJ	Major	Additive immunosuppressive effects by the combination of Azacitidine and Leflunomide.	Rheumatoid arthritis [FA20]	[14]
Anthrax vaccine	DM9GSWY	Moderate	Antagonize the effect of Azacitidine when combined with Anthrax vaccine.	Sepsis [1G40-1G41]	[24]
Azathioprine	DMMZSXQ	Moderate	Additive myelosuppressive effects by the combination of Azacitidine and Azathioprine.	Transplant rejection [NE84]	[18]
Ganciclovir	DM1MBYQ	Moderate	Additive myelosuppressive effects by the combination of Azacitidine and Ganciclovir.	Virus infection [1A24-1D9Z]	[18]
Valganciclovir	DMS2IUH	Moderate	Additive myelosuppressive effects by the combination of Azacitidine and Valganciclovir.	Virus infection [1A24-1D9Z]	[18]

References

• [1] Azacitidine FDA Label
• [2] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6796).
• [3] BDDCS applied to over 900 drugs
• [4] Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
• [5] Estimating the safe starting dose in phase I clinical trials and no observed effect level based on QSAR modeling of the human maximum recommended daily dose
• [6] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid l... Leukemia. 2009 Jun;23(6):1019-28.
• [7] A pilot pharmacokinetic study of oral azacitidine. Leukemia. 2008 Sep;22(9):1680-4.
• [8] Mycoplasma hyorhinis-encoded cytidine deaminase efficiently inactivates cytosine-based anticancer drugs. FEBS Open Bio. 2015 Aug 3;5:634-9.
• [9] Reduction of phosphoinositide-phospholipase C beta1 methylation predicts the responsiveness to azacitidine in high-risk MDS. Proc Natl Acad Sci U S A. 2009 Sep 29;106(39):16811-6. doi: 10.1073/pnas.0907109106. Epub 2009 Sep 10.
• [10] 15-hydroxyprostaglandin dehydrogenase is down-regulated in gastric cancer. Clin Cancer Res. 2009 Jul 15;15(14):4572-80. doi: 10.1158/1078-0432.CCR-08-2518. Epub 2009 Jul 7.
• [11] The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
• [12] Self-assembled 3D spheroids and hollow-fibre bioreactors improve MSC-derived hepatocyte-like cell maturation in vitro. Arch Toxicol. 2017 Apr;91(4):1815-1832.
• [13] Cerner Multum, Inc. "UK Summary of Product Characteristics.".
• [14] Product Information. Arava (leflunomide). Hoechst Marion-Roussel Inc, Kansas City, MO.
• [15] Product Information. Prolia (denosumab). Amgen USA, Thousand Oaks, CA.
• [16] Bennett CL, Nebeker JR, Samore MH, et al "The Research on Adverse Drug Events and Reports (RADAR) project." JAMA 293 (2005): 2131-40. [PMID: 15870417]
• [17] Product Information. Vumerity (diroximel fumarate). Alkermes, Inc, Cambridge, MA.
• [18] Cerner Multum, Inc. "Australian Product Information.".
• [19] Product Information. Gilenya (fingolimod). Novartis Pharmaceuticals, East Hanover, NJ.
• [20] Product Information. Ocrevus (ocrelizumab). Genentech, South San Francisco, CA.
• [21] Product Information. Synribo (omacetaxine). Teva Pharmaceuticals USA, North Wales, PA.
• [22] Product Information. Arcalyst (rilonacept). Regeneron Pharmaceuticals Inc, Tarrytown, NY.
• [23] Product Information. Cimzia (certolizumab). UCB Pharma Inc, Smyrna, GA.
• [24] CDC. Centers for Disease Control and Prevention/ "Recommendations of the advisory committtee on immunization practices (ACIP): use of vaccines and immune globulins in persons with altered immunocompetence." MMWR Morb Mortal Wkly Rep 42(RR-04) (1993): 1-18. [PMID: 20300058]