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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
6-((1-Methyl-4-nitro-1H-imidazol-5-yl)thio)-1H-purine
6-(1'-Methyl-4'-nitro-5'-imidazolyl)-mercaptopurine
Imuran (tn)
External Identifiers Not Available
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Azathioprinetablet50 mgoralSanis Health Inc2010-02-16Not applicableCanada
Azathioprinetablet50 mgoralBdh Inc.1998-10-082000-08-03Canada
Azathioprine Sodium for Injectionpowder for solution100 mgintravenousNovopharm LimitedNot applicableNot applicableCanada
Azathioprine-50tablet50 mgoralPro Doc Limitee2009-06-10Not applicableCanada
Imurantablet50 mg/1oralPrometheus Laboratories Inc.1968-03-202016-04-05Us
Imuranpowder for solution50 mgintravenousAspen Pharma Trading Limited2001-12-20Not applicableCanada
Imurantablet50 mgoralAspen Pharma Trading Limited1966-12-31Not applicableCanada
Imuran Inj 100mgpowder for solution100 mgintravenousGlaxo Wellcome Inc.1976-12-312000-10-25Canada
Mylan-azathioprinetablet50 mgoralMylan Pharmaceuticals Ulc1997-06-19Not applicableCanada
Ntp-azathioprinetablet50 mgoralTeva Canada LimitedNot applicableNot applicableCanada
Nu-azathioprinetablet50 mgoralNu Pharm IncNot applicableNot applicableCanada
Ratio-azathioprinetablet50 mgoralRatiopharm Inc Division Of Teva Canada Limited1998-02-232006-08-04Canada
Riva-azathioprine 50 mgtablet50 mgoralLaboratoire Riva Inc2000-05-122003-07-28Canada
Teva-azathioprinetablet50 mgoralTeva Canada Limited1998-02-02Not applicableCanada
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Apo-azathioprinetablet50 mgoralApotex Inc2000-10-17Not applicableCanada
Azasantablet100 mg/1oralSalix Pharmaceuticals2003-04-012016-04-05Us
Azasantablet75 mg/1oralSalix Pharmaceuticals2003-04-012016-04-05Us
Azathioprinetablet50 mg/1oralAmneal Pharmaceuticals of New York, LLC2015-02-022016-04-05Us
Azathioprinetablet50 mg/1oralCardinal Health1996-02-162016-04-05Us
Azathioprinetablet50 mg/1oralMylan Pharmaceuticals Inc.2009-12-282016-04-23Us
Azathioprinetablet50 mg/1oralRoxane Laboratories, Inc1996-02-162015-12-29Us
Azathioprinetablet50 mg/1oralGlenmark Pharmaceuticals, Inc1999-08-012016-04-05Us
Azathioprinetablet50 mg/1oralCardinal Health1996-02-162016-04-05Us
Azathioprinetablet50 1/1oralZydus Pharmaceuticals (USA) Inc.2007-07-112016-04-05Us
Azathioprinetablet50 mg/1oralPhysicians Total Care, Inc.2005-05-232016-04-05Us
Azathioprinetablet50 mg/1oralAmerican Health Packaging2008-02-222016-04-05Us
Azathioprinetablet50 mg/1oralMylan Institutional Inc.2010-07-232016-04-05Us
Azathioprinetablet50 mg/1oralCadila Healthcare Limited2007-07-112016-04-05Us
Azathioprinetablet50 mg/1oralAphena Pharma Solutions Tennessee, Llc1996-02-162016-04-05Us
Azathioprinetablet50 mg/1oralAidarex Pharmaceuticals LLC2007-07-112016-04-05Us
Azathioprinetablet50 mg/1oralRebel Distributors Corp..2007-07-112016-04-05Us
Azathioprinetablet50 mg/1oralRoxane Laboratories, Inc1996-02-162015-12-29Us
Azathioprinetablet50 mg/1oralbryant ranch prepack2008-02-222016-04-05Us
Azathioprinetablet50 mg/1oralNcs Health Care Of Ky, Inc Dba Vangard Labs1996-02-162016-04-23Us
Azathioprine Sodiuminjection, powder, lyophilized, for solution100 mg/10mLintravenousWest Ward Pharmaceuticals Corp1995-05-012016-04-23Us
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
UNIIMRK240IY2L
CAS number446-86-6
WeightAverage: 277.263
Monoisotopic: 277.038193193
Chemical FormulaC9H7N7O2S
InChI KeyInChIKey=LMEKQMALGUDUQG-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.
Related Articles
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 inhibitorNon-inhibitor0.907
CYP450 2D6 inhibitorNon-inhibitor0.9231
CYP450 2C19 inhibitorNon-inhibitor0.9025
CYP450 3A4 inhibitorNon-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
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
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
Tabletoral100 mg/1
Tabletoral75 mg/1
Tabletoral50 mg/1
Tabletoral50 1/1
Injection, powder, lyophilized, for solutionintravenous100 mg/10mL
Powder for solutionintravenous50 mg
Powder for solutionintravenous100 mg
Tabletoral50 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 References
  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:15705694 ]
  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:15899149 ]
  3. Gombar VK, Enslein K, Blake BW: Carcinogenicity of azathioprine: an S-AR investigation. Mutat Res. 1993 May;302(1):7-12. [PubMed:7683109 ]
External Links
ATC CodesL04AX01
AHFS Codes
  • 92:00.00
PDB EntriesNot Available
FDA labelDownload (212 KB)
MSDSDownload (75.4 KB)
Interactions
Drug Interactions
Drug
AcenocoumarolAzathioprine may decrease the anticoagulant activities of Acenocoumarol.
AllopurinolThe serum concentration of the active metabolites of Azathioprine can be increased when Azathioprine is used in combination with Allopurinol.
BalsalazideThe metabolism of Azathioprine can be decreased when combined with Balsalazide.
BenazeprilBenazepril may increase the myelosuppressive activities of Azathioprine.
CaptoprilCaptopril may increase the myelosuppressive activities of Azathioprine.
CilazaprilCilazapril may increase the myelosuppressive activities of Azathioprine.
CyclophosphamideAzathioprine may increase the hepatotoxic activities of Cyclophosphamide.
DenosumabThe risk or severity of adverse effects can be increased when Denosumab is combined with Azathioprine.
DicoumarolAzathioprine may decrease the anticoagulant activities of Dicoumarol.
EnalaprilEnalapril may increase the myelosuppressive activities of Azathioprine.
EnalaprilatEnalaprilat may increase the myelosuppressive activities of Azathioprine.
FebuxostatThe serum concentration of Azathioprine can be increased when it is combined with Febuxostat.
FosinoprilFosinopril may increase the myelosuppressive activities of Azathioprine.
LeflunomideThe risk or severity of adverse effects can be increased when Azathioprine is combined with Leflunomide.
LisinoprilLisinopril may increase the myelosuppressive activities of Azathioprine.
MercaptopurineAzathioprine may increase the myelosuppressive activities of Mercaptopurine.
MoexiprilMoexipril may increase the myelosuppressive activities of Azathioprine.
NatalizumabThe risk or severity of adverse effects can be increased when Azathioprine is combined with Natalizumab.
PerindoprilPerindopril may increase the myelosuppressive activities of Azathioprine.
PimecrolimusThe risk or severity of adverse effects can be increased when Pimecrolimus is combined with Azathioprine.
QuinaprilQuinapril may increase the myelosuppressive activities of Azathioprine.
RamiprilRamipril may increase the myelosuppressive activities of Azathioprine.
RibavirinThe serum concentration of the active metabolites of Azathioprine can be increased when Azathioprine is used in combination with Ribavirin.
RoflumilastRoflumilast may increase the immunosuppressive activities of Azathioprine.
Sipuleucel-TThe therapeutic efficacy of Sipuleucel-T can be decreased when used in combination with Azathioprine.
SulfamethoxazoleSulfamethoxazole may increase the myelosuppressive activities of Azathioprine.
TacrolimusThe risk or severity of adverse effects can be increased when Tacrolimus is combined with Azathioprine.
TofacitinibAzathioprine may increase the immunosuppressive activities of Tofacitinib.
TrandolaprilTrandolapril may increase the myelosuppressive activities of Azathioprine.
TrastuzumabTrastuzumab may increase the neutropenic activities of Azathioprine.
TrimethoprimTrimethoprim may increase the myelosuppressive activities of Azathioprine.
WarfarinAzathioprine may decrease the anticoagulant activities of Warfarin.
Food Interactions
  • Take with food to reduce irritation.

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Protein homodimerization activity
Specific Function:
Converts guanine to guanosine monophosphate, and hypoxanthine to inosine monophosphate. Transfers the 5-phosphoribosyl group from 5-phosphoribosylpyrophosphate onto the purine. Plays a central role in the generation of purine nucleotides through the purine salvage pathway.
Gene Name:
HPRT1
Uniprot ID:
P00492
Molecular Weight:
24579.155 Da
References
  1. Anstey A, Lear JT: Azathioprine: clinical pharmacology and current indications in autoimmune disorders. BioDrugs. 1998 Jan;9(1):33-47. [PubMed:18020555 ]
  2. Dubinsky MC: Azathioprine, 6-mercaptopurine in inflammatory bowel disease: pharmacology, efficacy, and safety. Clin Gastroenterol Hepatol. 2004 Sep;2(9):731-43. [PubMed:15354273 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Thiopurine s-methyltransferase activity
Specific Function:
Catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine.
Gene Name:
TPMT
Uniprot ID:
P51580
Molecular Weight:
28180.09 Da
References
  1. Sahasranaman S, Howard D, Roy S: Clinical pharmacology and pharmacogenetics of thiopurines. Eur J Clin Pharmacol. 2008 Aug;64(8):753-67. doi: 10.1007/s00228-008-0478-6. Epub 2008 May 28. [PubMed:18506437 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Xanthine oxidase activity
Specific Function:
Key enzyme in purine degradation. Catalyzes the oxidation of hypoxanthine to xanthine. Catalyzes the oxidation of xanthine to uric acid. Contributes to the generation of reactive oxygen species. Has also low oxidase activity towards aldehydes (in vitro).
Gene Name:
XDH
Uniprot ID:
P47989
Molecular Weight:
146422.99 Da
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:15354273 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Glutathione transferase activity
Specific Function:
Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles.
Gene Name:
GSTA1
Uniprot ID:
P08263
Molecular Weight:
25630.785 Da
References
  1. Link [Link]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Glutathione transferase activity
Specific Function:
Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles.
Gene Name:
GSTA2
Uniprot ID:
P09210
Molecular Weight:
25663.675 Da
References
  1. Link [Link]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Protein homodimerization activity
Specific Function:
Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles.
Gene Name:
GSTM1
Uniprot ID:
P09488
Molecular Weight:
25711.555 Da
References
  1. Link [Link]
Comments
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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:12