Mercaptopurine

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Mercaptopurine
Clinical data
Trade namesPurinethol, Purixan, others
Other names6-mercaptopurine (6-MP)
AHFS/Drugs.comMonograph
MedlinePlusa682653
License data
Pregnancy
category
  • D
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability5 to 37%
Metabolismxanthine oxidase
Elimination half-life60 to 120 min., longer for its active metabolites
Excretionkidney
Identifiers
  • 3,7-dihydropurine-6-thione
JSmol)
  • S=c1nc[nH]c2nc[nH]c12
  • InChI=1S/C5H4N4S/c10-5-3-4(7-1-6-3)8-2-9-5/h1-2H,(H2,6,7,8,9,10) checkY
  • Key:GLVAUDGFNGKCSF-UHFFFAOYSA-N checkY
  (verify)

Mercaptopurine (6-MP), sold under the brand name Purinethol among others, is a medication used for

acute lymphocytic leukemia (ALL), acute promyelocytic leukemia (APL), Crohn's disease, and ulcerative colitis.[1][2] For acute lymphocytic leukemia it is generally used with methotrexate.[1] It is taken orally.[1]

Common side effects include

thiopurine S-methyltransferase are at higher risk of side effects.[1] Use in pregnancy may harm the baby.[1]
Mercaptopurine is in the thiopurine and antimetabolite family of medications.[3][2]

Mercaptopurine was approved for medical use in the United States in 1953.[1] It is on the World Health Organization's List of Essential Medicines.[4]

Medical uses

It is used to treat

acute lymphocytic leukemia, Crohn's disease, and ulcerative colitis.[5]

Side effects

Some of the adverse reactions of taking mercaptopurine may include diarrhea, nausea, vomiting, loss of appetite, fatigue, stomach/abdominal pain, weakness, skin rash, darkening of the skin, and hair loss. Serious adverse reactions include mouth sores, fever, sore throat, easy bruising or bleeding, pinpoint red spots on the skin, yellowing of eyes or skin, dark urine, and painful or difficult urination. Other more serious side effects include black or tarry stools (melena), bloody stools, and bloody urine. Treatment is discontinued in up to 30% of patients due these effects but therapeutic drug monitoring of the biologically active metabolites, i.e. thiopurine nucleotides can help to optimize the efficacy and safety. Clinically, most hospitals resort to on-exchange LC-MS (liquid chromatography - mass spectrometry) but the newly developed approach of porous graphitic carbon based chromatography hyphenated with mass spectrometry appears superior with respect to patient care in this respect.[6]

Symptoms of allergic reaction to mercaptopurine include

swelling, dizziness, trouble breathing, and inflammation of the pancreas
.

In some cases, mercaptopurine may

suppress the production of blood cells, both white blood cells and red blood cells. It may be toxic to bone marrow
. Quarterly blood counts are necessary for people on mercaptopurine. People should stop taking the medication at least temporarily while considering alternate treatment if there is an unexplained, abnormally large drop in white blood cell count, or any other blood count.

Toxicity of mercaptopurine can be linked to genetic polymorphisms in thiopurine S-methyltransferase (TPMT), nudix hydrolase 15 (NUDT15),[7][8] and inosine triphosphate pyrophosphatase (ITPA). People with specific allele variants will require dose adjustments, especially for those with homozygous variant genotypes. Large differences of TPMT and NUDT15 among ethnicities in terms of variant allele frequency should be taken into consideration in clinical practice.[9] Caucasian people with a variant allele of the ITPA gene, experience higher rates of febrile neuropenia than people of other ethnic groups, due to differences in allelic frequencies among ethnicities.[10]

Precautions

Mercaptopurine can lower the body's ability to fight off infection. Those taking it should get permission from a doctor to receive immunizations and vaccinations. It is also recommended that, while on the drug, one should avoid those having recently received oral polio vaccine.

This drug was formerly not recommended during pregnancy and early evidence indicated pregnant women on the drug (or the related

suction abortion.[12] A more recent, larger study, however, performed by the Cancers et Surrisque Associe aux Maladies inflamatoires intestinales En France (CESAME) indicated an overall rate of congenital malformations not significantly greater than the general population in France.[13] The European Crohn's and Colitis Organisation (ECCO) concluded in a consensus paper in 2010 that while AZA and mercaptopurine have an FDA rating of D, new research in both animals and humans indicates that "thiopurines are safe and well tolerated during pregnancy."[14]

Mercaptopurine causes changes to

cytotoxic
drugs.

Drug interactions

Allopurinol inhibits xanthine oxidase, the enzyme that breaks down mercaptopurine. Those taking allopurinol (often used to prevent gout) are at risk for mercaptopurine toxicity. The dose should be reduced or allopurinol should be discontinued. Several published studies have demonstrated that the use of allopurinol in combination with low dose 6-MP helps reduce 6-MP levels, which are toxic to liver tissue, whilst increasing the therapeutic levels of 6-MP for some inflammatory conditions.

Mechanisms of action

Official information from the package insert for purinethol:[17]

  • Mercaptopurine is an antimetabolite antineoplastic, as such it interferes with normal metabolic processes within cells, typically by combining with enzymes, to disrupt DNA and RNA synthesis (cell-cycle S phase-specific) leading to death of rapidly proliferating cells, especially malignant ones. Specifically, Mercaptopurine is a purine antimetabolite or purine antagonist as such inhibits DNA synthesis by inhibiting the production of the purine containing nucleotides, adenine and guanine thus halting DNA synthesis.[18] Mercaptopurine also acts as an immunomodulator by inhibiting of several pathways in nucleic acid biosynthesis preventing proliferation of cells involved in the determination and amplification of the immune response.[19]
  • Mercaptopurine (6-MP) competes with the purine derivatives hypoxanthine and guanine for the enzyme HGPRT and is itself converted to thio inosine monophosphate (TIMP).
    • TIMP inhibits several chemical reactions involving
      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).
  • Animal tumors that are resistant to mercaptopurine often have lost the ability to convert mercaptopurine to TIMP. However, it is clear that resistance to mercaptopurine may be acquired by other means as well, particularly in human leukemias.
  • 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.

6-MP ribonucleotide inhibits purine nucleotide synthesis and metabolism by inhibiting an enzyme called

phosphoribosyl pyrophosphate amidotransferase (PRPP amidotransferase). Since this enzyme is the rate limiting factor for purine synthesis,[20] this alters the synthesis and function of RNA and DNA.[citation needed] Mercaptopurine interferes with nucleotide
interconversion and glycoprotein synthesis.

Pharmacogenetics

The enzyme

pharmacogenetics being translated into routine clinical care.[29]

History

6-MP was discovered by Nobel Prize–winning scientists

chemical weapons programs for the US Army and had been involved in the work that led to the discovery that nitrogen mustards could potentially be used as cancer drugs, and had become the director of Memorial in 1948.[31]

See also

References

  1. ^ a b c d e f g h i "Mercaptopurine". The American Society of Health-System Pharmacists. Archived from the original on 20 December 2016. Retrieved 8 December 2016.
  2. ^
    ISBN 9780857111562
    .
  3. S2CID 27475772
    .
  4. hdl:10665/325771
    . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  5. ^ "Mercaptopurine". The American Society of Health-System Pharmacists. Archived from the original on 2015-09-06. Retrieved Aug 28, 2015.
  6. S2CID 225287631
    .
  7. PMID 25624441
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  8. PMID 26878724
    .
  9. PMID 28088792
    .
  10. PMID 6404543
    .
  11. S2CID 25314258
    .
  12. PMID 10362152. Archived
    from the original on 2006-06-19.
  13. S2CID 25614617
    .
  14. PMID 21122490
    .
  15. S2CID 21675626
    .
  16. S2CID 45441636
    .
  17. ^ "PURINETHOL (mercaptopurine) tablet [Gate Pharmaceuticals]" (PDF). DailyMed. Gate Pharmaceuticals. August 2012. Archived from the original on 1 January 2014. Retrieved 31 December 2013.
  18. ^ "Chemotherapy".
  19. ^ Nielsen OH, Vainer B, Rask-Madsen J. Review article: the treatment of inflammatory bowel disease with 6-mercaptopurine or azathioprine. Aliment Pharmacol Ther. 2001 Nov;15(11):1699-708. doi: 10.1046/j.1365-2036.2001.01102.x. PMID 11683683.
  20. ^ Hansen, Barbara. "Purine and Pyrimidine Metabolism." USMLE STEP 1 Biochemistry and Medical Genetics Lecture Notes. 2010 ed. N.p.: Kaplan, 2010. 288-90. Print.
  21. PMID 19952870
    .
  22. PMID 24707136
    .
  23. PMID 17691917. Archived from the original
    on 2013-01-12.
  24. ^
    PMID 21270794
    .
  25. ISBN 978-3-8047-1763-3
    .
  26. PMID 17255139
    .
  27. ^ "Label: Mercaptopurine – mercaptopurine tablet". Archived from the original on 6 October 2015. Retrieved 11 March 2015.
  28. ^ "Purixan suspension". DailyMed. 9 April 2019. Retrieved 9 April 2020.
  29. PMID 20154640
    .
  30. ^ Bouton K (29 January 1989). "The Nobel Pair". The New York Times Magazine. Archived from the original on 2016-10-07.
  31. ^
    ISBN 978-1439170915
    .

Further reading

External links
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