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Identification
Name Mercaptopurine
Accession Number DB01033 (APRD01096)
Type small molecule
Groups approved
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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
6 MP
6-Mercaptopurine
Mercaptopurine Monohydrate
Mercapurin
MP
Salts Not Available
Brand names
Name Company
Ismipur
Leukerin
Leupurin
Mercaleukim
Mercaleukin
Mern
Puri-Nethol
Purimethol
Purinethol
Brand mixtures Not Available
Categories
  • Antineoplastic Agents
  • Antimetabolites
  • Immunosuppressive Agents
  • Nucleic Acid Synthesis Inhibitors
  • Purine analogues
  • Antimetabolites, Antineoplastic
CAS number 50-44-2
Weight Average: 152.177
Monoisotopic: 152.015666838
Chemical Formula C5H4N4S
InChI Key InChIKey=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)
Plain Text
IUPAC Name
6,7-dihydro-3H-purine-6-thione
SMILES
S=C1N=CNC2=C1NC=N2
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Purines and Purine Derivatives
Substructures
  • Pyrimidines and Derivatives
  • Imidazoles
  • Heterocyclic compounds
  • Aromatic compounds
  • Purines and Purine Derivatives
  • Cyanamides
Pharmacology
Indication For remission induction and maintenance therapy of acute lymphatic leukemia.
Pharmacodynamics Mercaptopurine 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 action Mercaptopurine 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).
Absorption Clinical 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 Not Available
Protein binding Plasma 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.
Route of elimination Not Available
Half life Triphasic: 45 minutes, 2.5 hours, and 10 hours.
Clearance Not Available
Toxicity Signs 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
Pathway Name SMPDB ID
Smp00427 Azathioprine Pathway SMP00427
Smp00428 Mercaptopurine Pathway SMP00428
Smp00430 Thioguanine Pathway SMP00430
Pharmacoeconomics
Manufacturers
  • Mylan pharmaceuticals inc
  • Prometheus laboratories inc
  • Roxane laboratories inc
  • Teva pharmaceuticals usa inc
Packagers
Dosage forms
Form Route Strength
Tablet Oral
Prices
Unit description Cost Unit
Mercaptopurine powder 33.97 USD g
Purinethol 50 mg tablet 6.09 USD tablet
Mercaptopurine 50 mg tablet 4.17 USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents Not Available
Properties
State solid
Experimental Properties
Property Value Source
melting point 313 dec °C PhysProp
water solubility 6.85E+004 mg/L YALKOWSKY,SH & DANNENFELSER,RM (1992)
logP 0.01 HANSCH,C & LEO,AJ (1985)
Predicted Properties
Property Value Source
water solubility 7.35e-01 g/l ALOGPS
logP -0.13 ALOGPS
logP -0.12 ChemAxon
logS -2.3 ALOGPS
pKa (strongest acidic) 9.5 ChemAxon
pKa (strongest basic) 2.99 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 3 ChemAxon
hydrogen donor count 2 ChemAxon
polar surface area 53.07 ChemAxon
rotatable bond count 0 ChemAxon
refractivity 43.6 ChemAxon
polarizability 14.04 ChemAxon
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D04931 Link_out
KEGG Compound C02380 Link_out
PubChem Compound 667490 Link_out
PubChem Substance 46506988 Link_out
ChemSpider 580869 Link_out
BindingDB 50200098 Link_out
ChEBI 2208 Link_out
ChEMBL 2208 Link_out
Therapeutic Targets Database DAP000147 Link_out
PharmGKB PA450379 Link_out
Drug Product Database 4723 Link_out
RxList http://www.rxlist.com/cgi/generic2/mercaptopurine.htm Link_out
Drugs.com http://www.drugs.com/cdi/mercaptopurine.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Mercaptopurine Link_out
ATC Codes
  • L01BB02
AHFS Codes
  • 10:00.00
PDB Entries Not Available
FDA label show (44.1 KB)
MSDS show (73.8 KB)
Interactions
Drug Interactions
Drug Interaction
Acenocoumarol Mercaptopurine may decrease the anticoagulant effect of acenocoumarol.
Allopurinol Allopurinol may increase the effect of thiopurine, mercaptopurine.
Aminosalicylic Acid Aminosalicylic acid may increase the toxicity of thiopurine, mercaptopurine.
Anisindione Mercaptopurine may decrease the anticoagulant effect of anisindione.
Atracurium The agent dereases the effect of the muscle relaxant
Dicumarol Mercaptopurine may decrease the anticoagulant effect of dicumarol.
Doxacurium chloride The agent dereases the effect of the muscle relaxant
Febuxostat Coadministration 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.
Mesalazine Mesalazine may increase the toxicity of thiopurine, mercaptopurine.
Metocurine The agent dereases the effect of the muscle relaxant
Mivacurium The agent dereases the effect of the muscle relaxant
Olsalazine Olsalazine may increase the toxicity of thiopurine, mercaptopurine.
Pancuronium The agent dereases the effect of the muscle relaxant
Sulfasalazine Sulfasalazine may increase the toxicity of thiopurine, mercaptopurine.
Thioguanine Complete cross resistance may occur.
Trastuzumab Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
Tubocurarine The agent dereases the effect of the muscle relaxant
Vecuronium The agent dereases the effect of the muscle relaxant
Warfarin Mercaptopurine 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

Pharmacological action: yes
Actions: inhibitor
Organism class: human
UniProt ID: P00492 Link_out
Gene: HPRT1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Enzymes

1. Thiopurine S-methyltransferase

Actions: substrate

Catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine

UniProt ID: P51580 Link_out
Gene: TPMT Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

This enzyme can be converted from the dehydrogenase form (D) to the oxidase form (O) irreversibly by proteolysis or reversibly through the oxidation of sulfhydryl groups

UniProt ID: P47989 Link_out
Gene: XDH Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Transporters

1. Solute carrier family 22 member 8

Actions: substrate, inhibitor

Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenadine. Transports benzylpenicillin (PCG), estrone- 3-sulfate (E1S), cimetidine (CMD), 2,4-dichloro-phenoxyacetate (2,4-D), p-amino-hippurate (PAH), acyclovir (ACV) and ochratoxin (OTA)

UniProt ID: Q8TCC7 Link_out
Gene: SLC22A8 Link_out
Protein Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

May be an organic anion pump relevant to cellular detoxification

UniProt ID: O15439 Link_out
Gene: ABCC4 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

Acts as a multispecific organic anion pump which can transport nucleotide analogs

UniProt ID: O15440 Link_out
Gene: ABCC5 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19