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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
SynonymsNot 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 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
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
    6-ThioguanineDetails
    Azathioprine
    6-MercaptopurineDetails
    Azathioprine
      6-thioguanylic acidDetails
      Azathioprine
        6-thioinosine triphosphateDetails
        Azathioprine
          6-thioinosinic acidDetails
          Azathioprine
            6-thioxanthylic acidDetails
            Azathioprine
              8-hydroxythioguanineDetails
              Azathioprine
                Thio-deoxyguanosine triphosphateDetails
                Azathioprine
                  Thioguanine diphosphateDetails
                  Azathioprine
                    Thioguanine triphosphateDetails
                    Azathioprine
                      6-thiouric acidDetails
                      Azathioprine
                        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 Action PathwayDrug actionSMP00427
                        Azathioprine Metabolism PathwayDrug metabolismSMP00645
                        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 solubility1.07e+00 g/lALOGPS
                        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 area118.1ChemAxon
                        rotatable bond count3ChemAxon
                        refractivity70.95ChemAxon
                        polarizability24.26ChemAxon
                        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.

                        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

                        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

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