Welcome to DrugBank 4.0! If you prefer, you can still go back to version 3.0.
Identification
NameMercaptopurine
Accession NumberDB01033  (APRD01096)
Typesmall molecule
Groupsapproved
Description

An antimetabolite antineoplastic agent with immunosuppressant properties. It interferes with nucleic acid synthesis by inhibiting purine metabolism and is used, usually in combination with other drugs, in the treatment of or in remission maintenance programs for leukemia. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
6 MPNot AvailableNot Available
6-MercaptopurineNot AvailableNot Available
6-MPNot AvailableNot Available
6-ThioxopurineNot AvailableNot Available
MercapurinNot AvailableNot Available
Salts
Name/CAS Structure Properties
Mercaptopurine monohydrate
Thumb Not applicable DBSALT001026
Brand names
NameCompany
LeukerinNot Available
PurinetholNot Available
Brand mixturesNot Available
Categories
CAS number50-44-2
WeightAverage: 152.177
Monoisotopic: 152.015666838
Chemical FormulaC5H4N4S
InChI KeyInChIKey=GLVAUDGFNGKCSF-UHFFFAOYSA-N
InChI
InChI=1S/C5H4N4S/c10-5-3-4(7-1-6-3)8-2-9-5/h1-2H,(H2,6,7,8,9,10)
IUPAC Name
6,7-dihydro-3H-purine-6-thione
SMILES
S=C1N=CNC2=C1NC=N2
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassImidazopyrimidines
SubclassPurines and Purine Derivatives
Direct parentPurinethiones
Alternative parentsPyrimidinethiones; Imidazoles; Polyamines
Substituentspyrimidinethione; pyrimidine; imidazole; azole; polyamine; organonitrogen compound
Classification descriptionThis compound belongs to the purinethiones. These are purines in which the purine moiety bears a thioketone.
Pharmacology
IndicationFor remission induction and maintenance therapy of acute lymphatic leukemia.
PharmacodynamicsMercaptopurine is one of a large series of purine analogues which interfere with nucleic acid biosynthesis and has been found active against human leukemias. It is an analogue of the purine bases adenine and hypoxanthine. It is not known exactly which of any one or more of the biochemical effects of mercaptopurine and its metabolites are directly or predominantly responsible for cell death.
Mechanism of actionMercaptopurine competes with hypoxanthine and guanine for the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) and is itself converted to thioinosinic acid (TIMP). This intracellular nucleotide inhibits several reactions involving inosinic acid (IMP), including the conversion of IMP to xanthylic acid (XMP) and the conversion of IMP to adenylic acid (AMP) via adenylosuccinate (SAMP). In addition, 6-methylthioinosinate (MTIMP) is formed by the methylation of TIMP. Both TIMP and MTIMP have been reported to inhibit glutamine-5-phosphoribosylpyrophosphate amidotransferase, the first enzyme unique to the de novo pathway for purine ribonucleotide synthesis. Experiments indicate that radiolabeled mercaptopurine may be recovered from the DNA in the form of deoxythioguanosine. Some mercaptopurine is converted to nucleotide derivatives of 6-thioguanine (6-TG) by the sequential actions of inosinate (IMP) dehydrogenase and xanthylate (XMP) aminase, converting TIMP to thioguanylic acid (TGMP).
AbsorptionClinical studies have shown that the absorption of an oral dose of mercaptopurine in humans is incomplete and variable, averaging approximately 50% of the administered dose. The factors influencing absorption are unknown.
Volume of distribution

The volume of distribution exceeded that of the total body water.

Protein bindingPlasma protein binding averages 19% over the concentration range 10 to 50 µg/mL (a concentration only achieved by intravenous administration of mercaptopurine at doses exceeding 5 to 10 mg/kg).
Metabolism

Hepatic. Degradation primarily by xanthine oxidase. The catabolism of mercaptopurine and its metabolites is complex. In humans, after oral administration of <sup>35</sup>S-6-mercaptopurine, urine contains intact mercaptopurine, thiouric acid (formed by direct oxidation by xanthine oxidase, probably via 6-mercapto-8-hydroxypurine), and a number of 6-methylated thiopurines. The methylthiopurines yield appreciable amounts of inorganic sulfate.

SubstrateEnzymesProduct
Mercaptopurine
6-Thioinosine 5'-monophosphateDetails
6-Thioinosine 5'-monophosphate
Thioxanthine monophosphateDetails
Thioxanthine monophosphate
Thioguanosine monophosphateDetails
Thioguanosine monophosphate
Methyl-thioguanosine monophosphateDetails
Thioguanosine monophosphate
    Thioguanosine diphosphateDetails
    Thioguanosine diphosphate
      Thioguanosine triphosphateDetails
      Thioguanosine diphosphate
        Thiodeoxyguanosine diphosphateDetails
        Thiodeoxyguanosine diphosphate
          Thiodeoxyguanosine triphosphateDetails
          6-Thioinosine 5'-monophosphate
          Methyl-thioinosine 5'-monophospateDetails
          6-Thioinosine 5'-monophosphate
            6-Mercaptopurine ribosideDetails
            6-Mercaptopurine riboside
            6-Methylmercaptopurine-ribosideDetails
            6-Methylmercaptopurine-riboside
            Methyl-thioinosine 5'-monophospateDetails
            Mercaptopurine
            8-hydroxythioguanineDetails
            Mercaptopurine
            Thiouric acidDetails
            Mercaptopurine
            MethylmercaptopurineDetails
            Route of eliminationNot Available
            Half lifeTriphasic: 45 minutes, 2.5 hours, and 10 hours.
            ClearanceNot Available
            ToxicitySigns and symptoms of overdosage may be immediate such as anorexia, nausea, vomiting, and diarrhea; or delayed such as myelosuppression, liver dysfunction, and gastroenteritis. The oral LD50 of mercaptopurine was determined to be 480 mg/kg in the mouse and 425 mg/kg in the rat.
            Affected organisms
            • Humans and other mammals
            Pathways
            PathwayCategorySMPDB ID
            Thioguanine Action PathwayDrug actionSMP00430
            Azathioprine Action PathwayDrug actionSMP00427
            Mercaptopurine Action PathwayDrug actionSMP00428
            Azathioprine Metabolism PathwayDrug metabolismSMP00645
            Mercaptopurine Metabolism PathwayDrug metabolismSMP00609
            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
            ADMET
            Predicted ADMET features
            Property Value Probability
            Human Intestinal Absorption + 0.8854
            Blood Brain Barrier + 0.8946
            Caco-2 permeable - 0.6556
            P-glycoprotein substrate Non-substrate 0.7141
            P-glycoprotein inhibitor I Non-inhibitor 0.9143
            P-glycoprotein inhibitor II Non-inhibitor 0.9848
            Renal organic cation transporter Non-inhibitor 0.8543
            CYP450 2C9 substrate Non-substrate 0.8607
            CYP450 2D6 substrate Non-substrate 0.8533
            CYP450 3A4 substrate Non-substrate 0.7949
            CYP450 1A2 substrate Inhibitor 0.7555
            CYP450 2C9 substrate Non-inhibitor 0.6955
            CYP450 2D6 substrate Non-inhibitor 0.8224
            CYP450 2C19 substrate Non-inhibitor 0.7472
            CYP450 3A4 substrate Non-inhibitor 0.8309
            CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.6635
            Ames test Non AMES toxic 0.5076
            Carcinogenicity Non-carcinogens 0.9369
            Biodegradation Not ready biodegradable 0.9972
            Rat acute toxicity 2.3684 LD50, mol/kg Not applicable
            hERG inhibition (predictor I) Weak inhibitor 0.9857
            hERG inhibition (predictor II) Non-inhibitor 0.8734
            Pharmacoeconomics
            Manufacturers
            • Mylan pharmaceuticals inc
            • Prometheus laboratories inc
            • Roxane laboratories inc
            • Teva pharmaceuticals usa inc
            Packagers
            Dosage forms
            FormRouteStrength
            TabletOral50 mg
            Prices
            Unit descriptionCostUnit
            Mercaptopurine powder33.97USDg
            Purinethol 50 mg tablet6.09USDtablet
            Mercaptopurine 50 mg tablet4.17USDtablet
            DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
            PatentsNot Available
            Properties
            Statesolid
            Experimental Properties
            PropertyValueSource
            melting point313 dec °CPhysProp
            water solubility6.85E+004 mg/LYALKOWSKY,SH & DANNENFELSER,RM (1992)
            logP0.01HANSCH,C & LEO,AJ (1985)
            Predicted Properties
            PropertyValueSource
            water solubility7.35e-01 g/lALOGPS
            logP-0.13ALOGPS
            logP-0.12ChemAxon
            logS-2.3ALOGPS
            pKa (strongest acidic)9.5ChemAxon
            pKa (strongest basic)2.99ChemAxon
            physiological charge0ChemAxon
            hydrogen acceptor count3ChemAxon
            hydrogen donor count2ChemAxon
            polar surface area53.07ChemAxon
            rotatable bond count0ChemAxon
            refractivity43.6ChemAxon
            polarizability14.04ChemAxon
            number of rings2ChemAxon
            bioavailability1ChemAxon
            rule of fiveYesChemAxon
            Ghose filterNoChemAxon
            Veber's ruleNoChemAxon
            MDDR-like ruleNoChemAxon
            Spectra
            SpectraNot Available
            References
            Synthesis ReferenceNot Available
            General ReferenceNot Available
            External Links
            ResourceLink
            KEGG DrugD04931
            KEGG CompoundC02380
            PubChem Compound667490
            PubChem Substance46506988
            ChemSpider580869
            BindingDB50200098
            ChEBI2208
            ChEMBLCHEMBL1425
            Therapeutic Targets DatabaseDAP000147
            PharmGKBPA450379
            Drug Product Database4723
            RxListhttp://www.rxlist.com/cgi/generic2/mercaptopurine.htm
            Drugs.comhttp://www.drugs.com/cdi/mercaptopurine.html
            WikipediaMercaptopurine
            ATC CodesL01BB02
            AHFS Codes
            • 10:00.00
            PDB EntriesNot Available
            FDA labelshow(44.1 KB)
            MSDSshow(73.8 KB)
            Interactions
            Drug Interactions
            Drug
            AcenocoumarolMercaptopurine may decrease the anticoagulant effect of acenocoumarol.
            AllopurinolAllopurinol may increase the effect of thiopurine, mercaptopurine.
            Aminosalicylic AcidAminosalicylic acid may increase the toxicity of thiopurine, mercaptopurine.
            AnisindioneMercaptopurine may decrease the anticoagulant effect of anisindione.
            AtracuriumThe agent dereases the effect of the muscle relaxant
            DicoumarolMercaptopurine may decrease the anticoagulant effect of dicumarol.
            Doxacurium chlorideThe agent dereases 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, mercaptopurine.
            MetocurineThe agent dereases the effect of the muscle relaxant
            MivacuriumThe agent dereases the effect of the muscle relaxant
            OlsalazineOlsalazine may increase the toxicity of thiopurine, mercaptopurine.
            PancuroniumThe agent dereases the effect of the muscle relaxant
            SulfasalazineSulfasalazine may increase the toxicity of thiopurine, mercaptopurine.
            TioguanineComplete cross resistance may occur.
            TrastuzumabTrastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
            TubocurarineThe agent dereases the effect of the muscle relaxant
            VecuroniumThe agent dereases the effect of the muscle relaxant
            WarfarinMercaptopurine may decrease the anticoagulant effect of warfarin.
            Food Interactions
            • Preferably on an empty stomach, drink plenty of liquids, avoid alcohol.

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

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

            Kind: protein

            Organism: Human

            Pharmacological action: unknown

            Actions: substrate

            Components

            Name UniProt ID Details
            Aldehyde oxidase Q06278 Details

            References:

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

            1. Solute carrier family 22 member 8

            Kind: protein

            Organism: Human

            Pharmacological action: unknown

            Actions: substrate inhibitor

            Components

            Name UniProt ID Details
            Solute carrier family 22 member 8 Q8TCC7 Details

            References:

            1. Ohtsuki S, Asaba H, Takanaga H, Deguchi T, Hosoya K, Otagiri M, Terasaki T: Role of blood-brain barrier organic anion transporter 3 (OAT3) in the efflux of indoxyl sulfate, a uremic toxin: its involvement in neurotransmitter metabolite clearance from the brain. J Neurochem. 2002 Oct;83(1):57-66. Pubmed
            2. Mori S, Takanaga H, Ohtsuki S, Deguchi T, Kang YS, Hosoya K, Terasaki T: Rat organic anion transporter 3 (rOAT3) is responsible for brain-to-blood efflux of homovanillic acid at the abluminal membrane of brain capillary endothelial cells. J Cereb Blood Flow Metab. 2003 Apr;23(4):432-40. Pubmed
            3. Kobayashi Y, Ohshiro N, Tsuchiya A, Kohyama N, Ohbayashi M, Yamamoto T: Renal transport of organic compounds mediated by mouse organic anion transporter 3 (mOat3): further substrate specificity of mOat3. Drug Metab Dispos. 2004 May;32(5):479-83. Pubmed

            2. Multidrug resistance-associated protein 4

            Kind: protein

            Organism: Human

            Pharmacological action: unknown

            Actions: substrate

            Components

            Name UniProt ID Details
            Multidrug resistance-associated protein 4 O15439 Details

            References:

            1. Chen ZS, Lee K, Kruh GD: Transport of cyclic nucleotides and estradiol 17-beta-D-glucuronide by multidrug resistance protein 4. Resistance to 6-mercaptopurine and 6-thioguanine. J Biol Chem. 2001 Sep 7;276(36):33747-54. Epub 2001 Jul 10. Pubmed

            3. Multidrug resistance-associated protein 5

            Kind: protein

            Organism: Human

            Pharmacological action: unknown

            Actions: substrate

            Components

            Name UniProt ID Details
            Multidrug resistance-associated protein 5 O15440 Details

            References:

            1. Wijnholds J, Mol CA, van Deemter L, de Haas M, Scheffer GL, Baas F, Beijnen JH, Scheper RJ, Hatse S, De Clercq E, Balzarini J, Borst P: Multidrug-resistance protein 5 is a multispecific organic anion transporter able to transport nucleotide analogs. Proc Natl Acad Sci U S A. 2000 Jun 20;97(13):7476-81. Pubmed

            4. Sodium/nucleoside cotransporter 2

            Kind: protein

            Organism: Human

            Pharmacological action: unknown

            Actions: substrate

            Components

            Name UniProt ID Details
            Sodium/nucleoside cotransporter 2 O43868 Details

            References:

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

            5. Solute carrier family 28 member 3

            Kind: protein

            Organism: Human

            Pharmacological action: unknown

            Actions: substrate

            Components

            Name UniProt ID Details
            Solute carrier family 28 member 3 Q9HAS3 Details

            References:

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

            6. Equilibrative nucleoside transporter 1

            Kind: protein

            Organism: Human

            Pharmacological action: unknown

            Actions: substrate

            Components

            Name UniProt ID Details
            Equilibrative nucleoside transporter 1 Q99808 Details

            References:

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

            7. Equilibrative nucleoside transporter 2

            Kind: protein

            Organism: Human

            Pharmacological action: unknown

            Actions: substrate

            Components

            Name UniProt ID Details
            Equilibrative nucleoside transporter 2 Q14542 Details

            References:

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

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