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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
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Imurantablet50 mgoralPrometheus Laboratories Inc.1968-03-20Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Imurantablet50 mgoralAspen Pharma Trading LimitedNot AvailableNot AvailableCanada 5f16b84899037e23705f146ff57e3794121879cb055f0954756d94bc690476b4
Imuranpowder for solution50 mgintravenousAspen Pharma Trading LimitedNot AvailableNot AvailableCanada 5f16b84899037e23705f146ff57e3794121879cb055f0954756d94bc690476b4
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Azathioprinetablet50 mgoralRoxane Laboratories, Inc1996-02-16Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Azathioprinetablet50 mgoralRoxane Laboratories, Inc1996-02-16Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Azathioprinetablet50 mgoralMylan Pharmaceuticals Inc.2009-12-28Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Azathioprinetablet50 mgoralNcs Health Care Of Ky, Inc Dba Vangard Labs1996-02-16Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Azathioprinetablet50 mgoralRebel Distributors Corp..2007-07-11Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Azathioprinetablet50 mgoralAidarex Pharmaceuticals LLC2007-07-11Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Azathioprinetablet50 mgoralAphena Pharma Solutions Tennessee, Llc1996-02-16Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Azathioprinetablet50 mgoralMylan Institutional Inc.2010-07-23Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Azathioprinetablet50 mgoralPhysicians Total Care, Inc.2005-05-23Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Azathioprinetablet50 mgoralCardinal Health1996-02-16Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Azathioprinetablet50 mgoralCardinal Health1996-02-16Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Azathioprinetablet50 mgoralbryant ranch prepack2008-02-22Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Azasantablet75 mgoralSalix Pharmaceuticals, Inc.2003-04-01Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Azasantablet100 mgoralSalix Pharmaceuticals, Inc.2003-04-01Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Azathioprinetablet50 mgoralCadila Healthcare Limited2007-07-11Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Azathioprinetablet50 mgoralAmerican Health Packaging2008-02-22Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Azathioprinetablet50 1oralZydus Pharmaceuticals (USA) Inc.2007-07-11Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Azathioprinetablet50 mgoralAmneal Pharmaceuticals of New York, LLC2015-02-02Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Azathioprinetablet50 mgoralSanis Health IncNot AvailableNot AvailableCanada 5f16b84899037e23705f146ff57e3794121879cb055f0954756d94bc690476b4
Over the Counter ProductsNot Available
International Brands
NameCompany
AzamunAscent
AzaninTanabe Mitsubishi Pharma
ImurekAspen
ImurelGlaxoSmithKline
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Azathioprine Sodium
Thumb
  • InChI Key: WISNYKIQFMKSDQ-UHFFFAOYSA-N
  • Monoisotopic Mass: 299.020137836
  • Average Mass: 299.244
DBSALT000012
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
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as diarylthioethers. These are organosulfur compounds containing a thioether group that is substituted by two aryl groups.
KingdomOrganic compounds
Super ClassOrganosulfur compounds
ClassThioethers
Sub ClassDiarylthioethers
Direct ParentDiarylthioethers
Alternative Parents
Substituents
  • Diarylthioether
  • 6-thiopurine
  • Purine
  • Imidazopyrimidine
  • Nitroimidazole
  • Imidolactam
  • Pyrimidine
  • N-substituted imidazole
  • Heteroaromatic compound
  • Imidazole
  • Azole
  • Organic nitro compound
  • Organic nitrite
  • C-nitro compound
  • Azacycle
  • Organoheterocyclic compound
  • Organic 1,3-dipolar compound
  • Propargyl-type 1,3-dipolar organic compound
  • Allyl-type 1,3-dipolar organic compound
  • Sulfenyl compound
  • Organic oxoazanium
  • Hydrocarbon derivative
  • Organic salt
  • Organonitrogen compound
  • Organic zwitterion
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
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
PropertyValueProbability
Human Intestinal Absorption+0.9607
Blood Brain Barrier+0.9226
Caco-2 permeable+0.5057
P-glycoprotein substrateNon-substrate0.7766
P-glycoprotein inhibitor INon-inhibitor0.8049
P-glycoprotein inhibitor IINon-inhibitor0.6683
Renal organic cation transporterNon-inhibitor0.8493
CYP450 2C9 substrateNon-substrate0.7861
CYP450 2D6 substrateNon-substrate0.8273
CYP450 3A4 substrateNon-substrate0.5944
CYP450 1A2 substrateNon-inhibitor0.9046
CYP450 2C9 substrateNon-inhibitor0.907
CYP450 2D6 substrateNon-inhibitor0.9231
CYP450 2C19 substrateNon-inhibitor0.9025
CYP450 3A4 substrateNon-inhibitor0.9733
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.7
Ames testAMES toxic0.9152
CarcinogenicityNon-carcinogens0.9182
BiodegradationNot ready biodegradable0.9576
Rat acute toxicity2.7519 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.7434
hERG inhibition (predictor II)Non-inhibitor0.8449
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
Powder for solutionintravenous50 mg
Tabletoral100 mg
Tabletoral50 1
Tabletoral50 mg
Tabletoral75 mg
Prices
Unit descriptionCostUnit
Azathioprine sod 100 mg vial132.0USD vial
Azathioprine powder28.15USD g
Azasan 100 mg tablet5.8USD tablet
Azasan 75 mg tablet4.34USD tablet
Imuran 50 mg Tablet2.76USD tablet
Azathioprine 50 mg tablet0.94USD tablet
Apo-Azathioprine 50 mg Tablet0.57USD tablet
Mylan-Azathioprine 50 mg Tablet0.57USD tablet
Novo-Azathioprine 50 mg Tablet0.57USD tablet
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 Solubility1.07 mg/mLALOGPS
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 RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
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
ATC CodesL04AX01
AHFS Codes
  • 92:00.00
PDB EntriesNot Available
FDA labelDownload (212 KB)
MSDSDownload (75.4 KB)
Interactions
Drug Interactions
Drug
AcenocoumarolMay diminish the anticoagulant effect of Vitamin K Antagonists.
AllopurinolAllopurinol may increase serum concentrations of the active metabolite(s) of AzaTHIOprine. More specifically, allopurinol may increase mercaptopurine serum concentrations and promote formation of active thioguanine nucleotides.
BenazeprilACE Inhibitors may enhance the myelosuppressive effect of AzaTHIOprine.
CaptoprilACE Inhibitors may enhance the myelosuppressive effect of AzaTHIOprine.
CilazaprilACE Inhibitors may enhance the myelosuppressive effect of AzaTHIOprine.
CyclophosphamideMay enhance the hepatotoxic effect of Cyclophosphamide.
DenosumabMay enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased.
EnalaprilACE Inhibitors may enhance the myelosuppressive effect of AzaTHIOprine.
FebuxostatMay increase the serum concentration of AzaTHIOprine.
FosinoprilACE Inhibitors may enhance the myelosuppressive effect of AzaTHIOprine.
LeflunomideImmunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased.
LisinoprilACE Inhibitors may enhance the myelosuppressive effect of AzaTHIOprine.
MercaptopurineAzaTHIOprine may enhance the myelosuppressive effect of Mercaptopurine.
MoexiprilACE Inhibitors may enhance the myelosuppressive effect of AzaTHIOprine.
NatalizumabImmunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased.
PerindoprilACE Inhibitors may enhance the myelosuppressive effect of AzaTHIOprine.
PimecrolimusMay enhance the adverse/toxic effect of Immunosuppressants.
QuinaprilACE Inhibitors may enhance the myelosuppressive effect of AzaTHIOprine.
RamiprilACE Inhibitors may enhance the myelosuppressive effect of AzaTHIOprine.
RibavirinRibavirin may increase serum concentrations of the active metabolite(s) of AzaTHIOprine. Specifically, concentrations of potentially myelotoxic methylated metabolites may be increased, while concentrations of active 6-thioguanine nucleotides may be decreased.
RoflumilastMay enhance the immunosuppressive effect of Immunosuppressants.
Sipuleucel-TImmunosuppressants may diminish the therapeutic effect of Sipuleucel-T.
SulfamethoxazoleMay enhance the myelosuppressive effect of AzaTHIOprine.
TofacitinibImmunosuppressants may enhance the immunosuppressive effect of Tofacitinib.
TrandolaprilACE Inhibitors may enhance the myelosuppressive effect of AzaTHIOprine.
TrastuzumabMay enhance the neutropenic effect of Immunosuppressants.
TrimethoprimTrimethoprim may enhance the myelosuppressive effect of AzaTHIOprine.
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. 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

2. 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

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

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