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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 KeyGLVAUDGFNGKCSF-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 35S-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
Not Available
Thioguanosine diphosphateDetails
Thioguanosine diphosphate
Not Available
Thioguanosine triphosphateDetails
Thioguanosine diphosphate
Not Available
Thiodeoxyguanosine diphosphateDetails
Thiodeoxyguanosine diphosphate
Not Available
Thiodeoxyguanosine triphosphateDetails
6-Thioinosine 5'-monophosphate
Methyl-thioinosine 5'-monophospateDetails
6-Thioinosine 5'-monophosphate
Not Available
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
Azathioprine Action PathwayDrug actionSMP00427
Thioguanine Action PathwayDrug actionSMP00430
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.

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

2. Amidophosphoribosyltransferase

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Amidophosphoribosyltransferase Q06203 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. doi: 10.1007/s00228-008-0478-6. Epub 2008 May 28. Pubmed
  2. Gaulton A, Bellis LJ, Bento AP, Chambers J, Davies M, Hersey A, Light Y, McGlinchey S, Michalovich D, Al-Lazikani B, Overington JP: ChEMBL: a large-scale bioactivity database for drug discovery. Nucleic Acids Res. 2012 Jan;40(Database issue):D1100-7. doi: 10.1093/nar/gkr777. Epub 2011 Sep 23. Pubmed

3. Inosine-5'-monophosphate dehydrogenase

Kind: protein group

Organism: Human

Pharmacological action: unknown

Actions: Inhibitor

Components

Name UniProt ID Details
Inosine-5'-monophosphate dehydrogenase 1 P20839 Details
Inosine-5'-monophosphate dehydrogenase 2 P12268 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. doi: 10.1007/s00228-008-0478-6. Epub 2008 May 28. Pubmed
  2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. 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. 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

Transporters

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

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