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Identification
NameAzathioprine
Accession NumberDB00993  (APRD00811)
TypeSmall Molecule
GroupsApproved
Description

An immunosuppressive antimetabolite pro-drug. It is an imidazolyl derivative of 6-mercaptopurine and many of its biological effects are similar to those of the parent compound. Azathioprine is converted into 6-mercaptopurine in the body where it blocks purine metabolism and DNA synthesis.

Structure
Thumb
Synonyms
SynonymLanguageCode
6-((1-Methyl-4-nitro-1H-imidazol-5-yl)thio)-1H-purineNot AvailableNot Available
6-(1'-Methyl-4'-nitro-5'-imidazolyl)-mercaptopurineNot AvailableNot Available
Imuran (tn)Not AvailableNot Available
Salts
Name/CAS Structure Properties
Azathioprine Sodium
Thumb
  • InChI Key: WISNYKIQFMKSDQ-UHFFFAOYSA-N
  • Monoisotopic Mass: 299.020137836
  • Average Mass: 299.244
DBSALT000012
Brand names
NameCompany
AzamunAscent
AzaninTanabe Mitsubishi Pharma
AzasanAAIPharma
ImuranGlaxoSmithKline
ImurekAspen
ImurelGlaxoSmithKline
Brand mixturesNot Available
Categories
CAS number446-86-6
WeightAverage: 277.263
Monoisotopic: 277.038193193
Chemical FormulaC9H7N7O2S
InChI KeyLMEKQMALGUDUQG-UHFFFAOYSA-N
InChI
InChI=1S/C9H7N7O2S/c1-15-4-14-7(16(17)18)9(15)19-8-5-6(11-2-10-5)12-3-13-8/h2-4H,1H3,(H,10,11,12,13)
IUPAC Name
6-[(1-methyl-4-nitro-1H-imidazol-5-yl)sulfanyl]-7H-purine
SMILES
CN1C=NC(=C1SC1=NC=NC2=C1NC=N2)[N+]([O-])=O
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassImidazopyrimidines
SubclassPurines and Purine Derivatives
Direct parentPurines and Purine Derivatives
Alternative parentsNitroimidazoles; Pyrimidines and Pyrimidine Derivatives; N-substituted Imidazoles; Nitro Compounds; Nitronic Acids; Organic Oxoazanium Compounds; Polyamines; Thioethers
Substituentsnitroimidazole; n-substituted imidazole; pyrimidine; imidazole; azole; nitro compound; nitronic acid; polyamine; thioether; organic oxoazanium; organonitrogen compound; amine
Classification descriptionThis compound belongs to the purines and purine derivatives. These are aromatic heterocyclic compounds containing a purine moiety, which is formed a pyrimidine-ring ring fused to an imidazole ring.
Pharmacology
IndicationFor use in rheumatoid arthritis, preventing renal transplant rejection, Crohn's disease, and colitis.
PharmacodynamicsAzathioprine is a chemotherapy drug, now rarely used for chemotherapy but more for immunosuppression in organ transplantation and autoimmune disease such as rheumatoid arthritis or inflammatory bowel disease or Crohn's disease. It is a pro-drug, converted in the body to the active metabolite 6-mercaptopurine. Azathioprine acts to inhibit purine synthesis necessary for the proliferation of cells, especially leukocytes and lymphocytes. It is a safe and effective drug used alone in certain autoimmune diseases, or in combination with other immunosuppressants in organ transplantation. Its most severe side effect is bone marrow suppression, and it should not be given in conjunction with purine analogues such as allopurinol. The enzyme thiopurine S-methyltransferase (TPMT) deactivates 6-mercaptopurine. Genetic polymorphisms of TPMT can lead to excessive drug toxicity, thus assay of serum TPMT may be useful to prevent this complication.
Mechanism of actionAzathioprine antagonizes purine metabolism and may inhibit synthesis of DNA, RNA, and proteins. It may also interfere with cellular metabolism and inhibit mitosis. Its mechanism of action is likely due to incorporation of thiopurine analogues into the DNA structure, causing chain termination and cytotoxicity.
AbsorptionWell absorbed following oral administration.
Volume of distributionNot Available
Protein bindingAzathioprine and the metabolite mercaptopurine are moderately bound to serum proteins (30%).
Metabolism

Primarily converted to the active metabolites 6-mercaptopurine and 6-thioinosinic acid via a non-enzymatica process and glutathione transferases. Activation of 6-mercaptopurine occurs via hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and a series of multi-enzymatic processes involving kinases to form 6-thioguanine nucleotides (6-TGNs) as major metabolites

SubstrateEnzymesProduct
Azathioprine
S-methylazathioprineDetails
Azathioprine
Not Available
6-ThioguanineDetails
Azathioprine
6-MercaptopurineDetails
Azathioprine
Not Available
6-thioguanylic acidDetails
Azathioprine
Not Available
6-thioinosine triphosphateDetails
Azathioprine
Not Available
6-thioinosinic acidDetails
Azathioprine
Not Available
6-thioxanthylic acidDetails
Azathioprine
Not Available
8-hydroxythioguanineDetails
Azathioprine
Not Available
Thio-deoxyguanosine triphosphateDetails
Azathioprine
Not Available
Thioguanine diphosphateDetails
Azathioprine
Not Available
Thioguanine triphosphateDetails
Azathioprine
Not Available
6-thiouric acidDetails
Azathioprine
Not Available
6-Thioxanthine 5'-monophosphateDetails
Route of eliminationBoth compounds are rapidly eliminated from blood and are oxidized or methylated in erythrocytes and liver; no azathioprine or mercaptopurine is detectable in urine after 8 hours.
Half lifeNot Available
ClearanceNot Available
ToxicityThe oral LD50 for single doses of azathioprine in mice and rats are 2500 mg/kg and 400 mg/kg, respectively. Very large doses of this antimetabolite may lead to marrow hypoplasia, bleeding, infection, and death.
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Azathioprine Metabolism PathwayDrug metabolismSMP00645
Azathioprine Action PathwayDrug actionSMP00427
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug Reactions
Interacting Gene/EnzymeSNP RS IDAllele nameDefining changeAdverse ReactionReference(s)
Thiopurine S-methyltransferase
Gene symbol: TPMT
UniProt: P51580
rs1800462 TMPT*2G AlleleHepatotoxicity16509759
Thiopurine S-methyltransferase
Gene symbol: TPMT
UniProt: P51580
rs1800460 TMPT*3AA AlleleHepatotoxicity16509759
Thiopurine S-methyltransferase
Gene symbol: TPMT
UniProt: P51580
rs1142345 TMPT*3CG AlleleHepatotoxicity16509759
Thiopurine S-methyltransferase
Gene symbol: TPMT
UniProt: P51580
rs1142345 TPMT*3CT > CPatients with CC or CT genotype have decreased inactivation of thiopurines and increased risk of toxicity22846425
Thiopurine S-methyltransferase
Gene symbol: TPMT
UniProt: P51580
rs1142345 TPMT*3CT > CPatients with CC or CT genotype have decreased inactivation of thiopurines and increased risk of toxicity9103127
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9607
Blood Brain Barrier + 0.9226
Caco-2 permeable + 0.5057
P-glycoprotein substrate Non-substrate 0.7766
P-glycoprotein inhibitor I Non-inhibitor 0.8049
P-glycoprotein inhibitor II Non-inhibitor 0.6683
Renal organic cation transporter Non-inhibitor 0.8493
CYP450 2C9 substrate Non-substrate 0.7861
CYP450 2D6 substrate Non-substrate 0.8273
CYP450 3A4 substrate Non-substrate 0.5944
CYP450 1A2 substrate Non-inhibitor 0.9046
CYP450 2C9 substrate Non-inhibitor 0.907
CYP450 2D6 substrate Non-inhibitor 0.9231
CYP450 2C19 substrate Non-inhibitor 0.9025
CYP450 3A4 substrate Non-inhibitor 0.9733
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.7
Ames test AMES toxic 0.9152
Carcinogenicity Non-carcinogens 0.9182
Biodegradation Not ready biodegradable 0.9576
Rat acute toxicity 2.7519 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.7434
hERG inhibition (predictor II) Non-inhibitor 0.8449
Pharmacoeconomics
Manufacturers
  • Aaipharma llc
  • Mylan pharmaceuticals inc
  • Roxane laboratories inc
  • Zydus pharmaceuticals usa inc
  • Prometheus laboratories inc
  • Bedford laboratories div ben venue laboratories inc
Packagers
Dosage forms
FormRouteStrength
Injection, powder, for solutionIntravenous100 mg
TabletOral50 mg, 75 mg, 100 mg
Prices
Unit descriptionCostUnit
Azathioprine sod 100 mg vial132.0USDvial
Azathioprine powder28.15USDg
Azasan 100 mg tablet5.8USDtablet
Azasan 75 mg tablet4.34USDtablet
Imuran 50 mg Tablet2.76USDtablet
Azathioprine 50 mg tablet0.94USDtablet
Apo-Azathioprine 50 mg Tablet0.57USDtablet
Mylan-Azathioprine 50 mg Tablet0.57USDtablet
Novo-Azathioprine 50 mg Tablet0.57USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point243.5 °CPhysProp
water solubilityInsoluble FDA label
logP0.10HANSCH,C ET AL. (1995)
pKa7.87 (at 25 °C)MITRA,AK & NARURKAR,MM (1986)
Predicted Properties
PropertyValueSource
Water Solubility1.07ALOGPS
logP0.84ALOGPS
logP1.17ChemAxon
logS-2.4ALOGPS
pKa (Strongest Acidic)8.65ChemAxon
pKa (Strongest Basic)4ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area118.1 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity70.95 m3·mol-1ChemAxon
Polarizability24.26 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis ReferenceNot Available
General Reference
  1. Konstantopoulou M, Belgi A, Griffiths KD, Seale JR, Macfarlane AW: Azathioprine-induced pancytopenia in a patient with pompholyx and deficiency of erythrocyte thiopurine methyltransferase. BMJ. 2005 Feb 12;330(7487):350-1. Pubmed
  2. Woodroffe R, Yao GL, Meads C, Bayliss S, Ready A, Raftery J, Taylor RS: Clinical and cost-effectiveness of newer immunosuppressive regimens in renal transplantation: a systematic review and modelling study. Health Technol Assess. 2005 May;9(21):1-179, iii-iv. Pubmed
  3. Gombar VK, Enslein K, Blake BW: Carcinogenicity of azathioprine: an S-AR investigation. Mutat Res. 1993 May;302(1):7-12. Pubmed
External Links
ResourceLink
KEGG DrugD00238
KEGG CompoundC06837
PubChem Compound2265
PubChem Substance46508252
ChemSpider2178
ChEBI2948
ChEMBLCHEMBL1542
Therapeutic Targets DatabaseDAP000782
PharmGKBPA448515
Drug Product Database2242907
RxListhttp://www.rxlist.com/cgi/generic/azathioprine.htm
Drugs.comhttp://www.drugs.com/cdi/azathioprine.html
WikipediaAzathioprine
ATC CodesL04AX01
AHFS Codes
  • 92:00.00
PDB EntriesNot Available
FDA labelshow(212 KB)
MSDSshow(75.4 KB)
Interactions
Drug Interactions
Drug
AcenocoumarolAzathioprine may decrease the anticoagulant effect of acenocoumarol.
AllopurinolAllopurinol may increase the effect of thiopurine, azathioprine.
Aminosalicylic AcidAminosalicylic acid may increase the toxicity of thiopurine, azathioprine.
AnisindioneAzathioprine may decrease the anticoagulant effect of anisindione.
AtracuriumThe agent decreases the effect of the muscle relaxant
Canakinumabresults in increased immunosuppressive effects; increases the risk of infection.
DicoumarolAzathioprine may decrease the anticoagulant effect of dicumarol.
Doxacurium chlorideThe agent decreases the effect of the muscle relaxant
FebuxostatCoadministration of febuxostat with xanthine oxidase substrate drugs (azathioprine, mercaptopurine or theophylline) could increase plasma concentrations of these drugs, since these drugs are metabolized by xanthine oxidase, resulting in severe toxicity; hence their concomitant use is contraindicated. Since febuxostat does not inhibit or induce cytochrome P450 enzymes it lacks significant drug interactions with other drugs metabolized of these enzymes.
MesalazineMesalazine may increase the toxicity of thiopurine, azathioprine.
MetocurineThe agent decreases the effect of the muscle relaxant
MivacuriumThe agent decreases the effect of the muscle relaxant
OlsalazineOlsalazine may increase the toxicity of thiopurine, azathioprine.
PancuroniumThe agent decreases the effect of the muscle relaxant
Rilonaceptresults in increased immunosuppressive effects; increases the risk of infection.
SulfasalazineSulfasalazine may increase the toxicity of thiopurine, azathioprine.
TrandolaprilTrandolapril may increase the risk of neutropenia. Monitor for increased toxic effects of Azathioprine if Trandolapril is initiated or dose increased.
TrastuzumabTrastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
TubocurarineThe agent decreases the effect of the muscle relaxant
VecuroniumThe agent decreases the effect of the muscle relaxant
WarfarinAzathioprine may decrease the anticoagulant effect of warfarin.
Food Interactions
  • Take with food to reduce irritation.

Targets

1. Hypoxanthine-guanine phosphoribosyltransferase

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Hypoxanthine-guanine phosphoribosyltransferase P00492 Details

References:

  1. Anstey A, Lear JT: Azathioprine: clinical pharmacology and current indications in autoimmune disorders. BioDrugs. 1998 Jan;9(1):33-47. Pubmed
  2. Dubinsky MC: Azathioprine, 6-mercaptopurine in inflammatory bowel disease: pharmacology, efficacy, and safety. Clin Gastroenterol Hepatol. 2004 Sep;2(9):731-43. Pubmed

Enzymes

1. Xanthine dehydrogenase/oxidase

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Xanthine dehydrogenase/oxidase P47989 Details

References:

  1. Dubinsky MC: Azathioprine, 6-mercaptopurine in inflammatory bowel disease: pharmacology, efficacy, and safety. Clin Gastroenterol Hepatol. 2004 Sep;2(9):731-43. Pubmed

2. Thiopurine S-methyltransferase

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Thiopurine S-methyltransferase P51580 Details

References:

  1. Sahasranaman S, Howard D, Roy S: Clinical pharmacology and pharmacogenetics of thiopurines. Eur J Clin Pharmacol. 2008 Aug;64(8):753-67. Epub 2008 May 28. Pubmed

3. Glutathione S-transferase A1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Glutathione S-transferase A1 P08263 Details

References:

  1. https://www.pharmgkb.org/pathway/PA2040

4. Glutathione S-transferase A2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Glutathione S-transferase A2 P09210 Details

References:

  1. https://www.pharmgkb.org/pathway/PA2040

5. Glutathione S-transferase Mu 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Glutathione S-transferase Mu 1 P09488 Details

References:

  1. https://www.pharmgkb.org/pathway/PA2040

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