Mercaptopurine Explained

Verifiedrevid:462248688
Width:200
Tradename:Purinethol, Purixan, others
Synonyms:6-mercaptopurine (6-MP)
Dailymedid:Mercaptopurine
Routes Of Administration:By mouth
Atc Prefix:L01
Atc Suffix:BB02
Legal Eu:Rx-only
Legal Eu Comment:[1]
Legal Status:Rx-only
Bioavailability:5 to 37%
Metabolism:xanthine oxidase
Elimination Half-Life:60 to 120 min., longer for its active metabolites
Excretion:kidney
Iuphar Ligand:7226
Cas Number:50-44-2
Pubchem:667490
Drugbank:DB01033
Chemspiderid:580869
Unii:PKK6MUZ20G
Kegg:D04931
Chebi:50667
Chembl:1425
Iupac Name:3,7-dihydropurine-6-thione
C:5
H:4
N:4
S:1
Smiles:S=c1nc[nH]c2nc[nH]c12
Stdinchi:1S/C5H4N4S/c10-5-3-4(7-1-6-3)8-2-9-5/h1-2H,(H2,6,7,8,9,10)
Stdinchikey:GLVAUDGFNGKCSF-UHFFFAOYSA-N

Mercaptopurine (6-MP), sold under the brand name Purinethol among others, is a medication used for cancer and autoimmune diseases. Specifically it is used to treat acute lymphocytic leukemia (ALL), acute promyelocytic leukemia (APL), Crohn's disease, and ulcerative colitis. For acute lymphocytic leukemia it is generally used with methotrexate. It is taken orally.[2]

Common side effects include bone marrow suppression, liver toxicity, vomiting, and loss of appetite.[2] Other serious side effects include an increased risk of future cancer and pancreatitis.[2] Those with a genetic deficiency in thiopurine S-methyltransferase are at higher risk of side effects.[2] Use in pregnancy may harm the baby.[2] Mercaptopurineis in the thiopurine and antimetabolite family of medications.[3] [4]

Mercaptopurine was approved for medical use in the United States in 1953.[2] It is on the World Health Organization's List of Essential Medicines.[5]

Medical uses

It is used to treat acute lymphocytic leukemia, Crohn's disease, and ulcerative colitis.[6]

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.[7]

Symptoms of allergic reaction to mercaptopurine include rash, itching, 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),[8] [9] 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.[10] 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.[11]

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 azathioprine) showed a seven-fold incidence of fetal abnormalities as well as a 20-fold increase in miscarriage.[12] There were also anecdotal reports linking mercaptopurine with spontaneous abortion, leading to the US FDA rating both AZA and mercaptopurine as category D drugs. However, Davis et al. 1999 found mercaptopurine, compared to methotrexate, was ineffective as a single-agent abortifacient; every woman in the mercaptopurine arm of the study had fetal cardiac activity at follow-up (two weeks later) and was given a suction abortion.[13] 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.[14] 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."[15]

Mercaptopurine causes changes to chromosomes in animals and humans, though a study in 1990[16] found, "while the carcinogenic potential of 6-MP cannot be precluded, it can be only very weak or marginal." Another study in 1999[17] noted an increased risk of developing leukemia when taking large doses of 6-MP with other 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:[18]

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,[21] this alters the synthesis and function of RNA and DNA. Mercaptopurine interferes with nucleotide interconversion and glycoprotein synthesis.

Pharmacogenetics

The enzyme thiopurine S-methyltransferase (TPMT) is responsible, in part, for the inactivation of 6-mercaptopurine. TPMT catalyzes the methylation of 6-mercaptopurine into the inactive metabolite 6-methylmercaptopurine – this methylation prevents mercaptopurine from further conversion into active, cytotoxic thioguanine nucleotide (TGN) metabolites.[22] [23] [24] Certain genetic variations within the TPMT gene can lead to decreased or absent TPMT enzyme activity, and individuals who are homozygous or heterozygous for these types of genetic variations may have increased levels of TGN metabolites and an increased risk of severe bone marrow suppression (myelosuppression) when receiving mercaptopurine.[25] In many ethnicities, TPMT polymorphisms that result in decreased or absent TPMT activity occur with a frequency of approximately 5%, meaning that about 0.25% of people are homozygous for these variants.[25] [26] However, an assay of TPMT activity in red blood cells or a TPMT genetic test can identify people with reduced TPMT activity, allowing for the adjustment of mercaptopurine dose or avoidance of the drug entirely.[25] [27] The FDA-approved drug label for mercaptopurine recommends testing for TPMT activity to identify people at risk for myelotoxicity.[28] [29] Testing for TPMT activity is an example of pharmacogenetics being translated into routine clinical care.[30]

History

6-MP was discovered by Nobel Prize–winning scientists Gertrude B. Elion and George H. Hitchings at Burroughs Wellcome in Tuckahoe, New York,[31] and was clinically developed in collaboration with investigators at Memorial Hospital (now Memorial Sloan Kettering Cancer Center in New York City).[32] The collaboration was initiated by Cornelius P. Rhoads, who had run 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.[32]

Further reading

Notes and References

  1. Web site: Xaluprine EPAR . European Medicines Agency . 30 April 2009 . 25 June 2024.
  2. Web site: Mercaptopurine. The American Society of Health-System Pharmacists. 8 December 2016. live. https://web.archive.org/web/20161220192655/https://www.drugs.com/monograph/mercaptopurine.html. 20 December 2016.
  3. Sahasranaman S, Howard D, Roy S . Clinical pharmacology and pharmacogenetics of thiopurines . European Journal of Clinical Pharmacology . 64 . 8 . 753–67 . August 2008 . 18506437 . 10.1007/s00228-008-0478-6 . 27475772 .
  4. Book: British national formulary : BNF 69. 2015. British Medical Association. 9780857111562. 590. 69.
  5. Book: ((World Health Organization)) . World Health Organization model list of essential medicines: 21st list 2019 . 2019 . 10665/325771 . World Health Organization . World Health Organization . Geneva . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO . free .
  6. Web site: Mercaptopurine. The American Society of Health-System Pharmacists. Aug 28, 2015. live. https://web.archive.org/web/20150906153856/http://www.drugs.com/monograph/mercaptopurine.html. 2015-09-06.
  7. Pecher D, Zelinkova Z, Lucenicova J, Peppelenbosch M, Dokupilova S, Mikusova V, Mikus P . Porous graphitic carbon based chromatography hyphenated with mass spectrometry: A new strategy for profiling thiopurine nucleotides in patients with inflammatory bowel diseases . Analytica Chimica Acta . 1137 . 1137 . 64–73 . November 2020 . 33153610 . 10.1016/j.aca.2020.08.064 . 2020AcAC.1137...64P . 225287631 .
  8. Yang JJ, Landier W, Yang W, Liu C, Hageman L, Cheng C, Pei D, Chen Y, Crews KR, Kornegay N, Wong FL, Evans WE, Pui CH, Bhatia S, Relling MV . 6 . Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia . Journal of Clinical Oncology . 33 . 11 . 1235–42 . April 2015 . 25624441 . 4375304 . 10.1200/jco.2014.59.4671 .
  9. Moriyama T, Nishii R, Perez-Andreu V, Yang W, Klussmann FA, Zhao X, Lin TN, Hoshitsuki K, Nersting J, Kihira K, Hofmann U, Komada Y, Kato M, McCorkle R, Li L, Koh K, Najera CR, Kham SK, Isobe T, Chen Z, Chiew EK, Bhojwani D, Jeffries C, Lu Y, Schwab M, Inaba H, Pui CH, Relling MV, Manabe A, Hori H, Schmiegelow K, Yeoh AE, Evans WE, Yang JJ . 6 . NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity . Nature Genetics . 48 . 4 . 367–73 . April 2016 . 26878724 . 5029084 . 10.1038/ng.3508 .
  10. Yin D, Xia X, Zhang J, Zhang S, Liao F, Zhang G, Zhang Y, Hou Q, Yang X, Wang H, Ma Z, Wang H, Zhu Y, Zhang W, Wang Y, Liu B, Wang L, Xu H, Shu Y . 6 . Impact of NUDT15 polymorphisms on thiopurines-induced myelotoxicity and thiopurines tolerance dose . Oncotarget . 8 . 8 . 13575–13585 . February 2017 . 28088792 . 5355121 . 10.18632/oncotarget.14594 .
  11. Esses SI, Morley TP . Spinal arachnoiditis . The Canadian Journal of Neurological Sciences . 10 . 1 . 2–10 . February 1983 . 6404543 . 10.1017/s0317167100044486 . free .
  12. Nørgård B, Pedersen L, Fonager K, Rasmussen SN, Sørensen HT . Azathioprine, mercaptopurine and birth outcome: a population-based cohort study . Alimentary Pharmacology & Therapeutics . 17 . 6 . 827–34 . March 2003 . 12641505 . 10.1046/j.1365-2036.2003.01537.x . 25314258 . free .
  13. Davis AR, Miller L, Tamimi H, Gown A . Methotrexate compared with mercaptopurine for early induced abortion . Obstetrics and Gynecology . 93 . 6 . 904–9 . June 1999 . 10362152 . 10.1016/S0029-7844(98)00569-9 . live . https://web.archive.org/web/20060619115203/http://www.greenjournal.org/cgi/content/full/93/6/904 . 2006-06-19 .
  14. Coelho J, Beaugerie L, Colombel JF, Hébuterne X, Lerebours E, Lémann M, Baumer P, Cosnes J, Bourreille A, Gendre JP, Seksik P, Blain A, Metman EH, Nisard A, Cadiot G, Veyrac M, Coffin B, Dray X, Carrat F, Marteau P . 6 . Pregnancy outcome in patients with inflammatory bowel disease treated with thiopurines: cohort from the CESAME Study . Gut . 60 . 2 . 198–203 . February 2011 . 21115547 . 10.1136/gut.2010.222893 . 25614617 .
  15. Van Assche G, Dignass A, Reinisch W, van der Woude CJ, Sturm A, De Vos M, Guslandi M, Oldenburg B, Dotan I, Marteau P, Ardizzone A, Baumgart DC, D'Haens G, Gionchetti P, Portela F, Vucelic B, Söderholm J, Escher J, Koletzko S, Kolho KL, Lukas M, Mottet C, Tilg H, Vermeire S, Carbonnel F, Cole A, Novacek G, Reinshagen M, Tsianos E, Herrlinger K, Oldenburg B, Bouhnik Y, Kiesslich R, Stange E, Travis S, Lindsay J . 6 . The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Special situations . Journal of Crohn's & Colitis . 4 . 1 . 63–101 . February 2010 . 21122490 . 10.1016/j.crohns.2009.09.009 . free .
  16. Maekawa A, Nagaoka T, Onodera H, Matsushima Y, Todate A, Shibutani M, Ogasawara H, Kodama Y, Hayashi Y . 6 . Two-year carcinogenicity study of 6-mercaptopurine in F344 rats . Journal of Cancer Research and Clinical Oncology . 116 . 3 . 245–50 . May 1990 . 2370249 . 10.1007/BF01612898 . 21675626 .
  17. Bo J, Schrøder H, Kristinsson J, Madsen B, Szumlanski C, Weinshilboum R, Andersen JB, Schmiegelow K . 6 . Possible carcinogenic effect of 6-mercaptopurine on bone marrow stem cells: relation to thiopurine metabolism . Cancer . 86 . 6 . 1080–6 . September 1999 . 10491537 . 10.1002/(SICI)1097-0142(19990915)86:6<1080::AID-CNCR26>3.0.CO;2-5 . 45441636 . free .
  18. Web site: PURINETHOL (mercaptopurine) tablet [Gate Pharmaceuticals]]. DailyMed. Gate Pharmaceuticals. August 2012. PDF. 31 December 2013. live. https://web.archive.org/web/20140101024906/http://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=f9af557d-37bf-4078-888e-37c086dfc6e9&type=pdf&name=f9af557d-37bf-4078-888e-37c086dfc6e9. 1 January 2014.
  19. Web site: Chemotherapy.
  20. 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.
  21. Hansen, Barbara. "Purine and Pyrimidine Metabolism." USMLE STEP 1 Biochemistry and Medical Genetics Lecture Notes. 2010 ed. N.p.: Kaplan, 2010. 288-90. Print.
  22. Zaza G, Cheok M, Krynetskaia N, Thorn C, Stocco G, Hebert JM, McLeod H, Weinshilboum RM, Relling MV, Evans WE, Klein TE, Altman RB . 6 . Thiopurine pathway . Pharmacogenetics and Genomics . 20 . 9 . 573–4 . September 2010 . 19952870 . 3098750 . 10.1097/FPC.0b013e328334338f .
  23. Stocco G, Pelin M, Franca R, De Iudicibus S, Cuzzoni E, Favretto D, Martelossi S, Ventura A, Decorti G . 6 . Pharmacogenetics of azathioprine in inflammatory bowel disease: a role for glutathione-S-transferase? . World Journal of Gastroenterology . 20 . 13 . 3534–41 . April 2014 . 24707136 . 3974520 . 10.3748/wjg.v20.i13.3534 . free .
  24. Fujita K, Sasaki Y . Pharmacogenomics in drug-metabolizing enzymes catalyzing anticancer drugs for personalized cancer chemotherapy . Current Drug Metabolism . 8 . 6 . 554–62 . August 2007 . 17691917 . 10.2174/138920007781368890 . dead . https://archive.today/20130112103320/http://www.bentham-direct.org/pages/content.php?CDM/2007/00000008/00000006/0002F.SGM . 2013-01-12 .
  25. Relling MV, Gardner EE, Sandborn WJ, Schmiegelow K, Pui CH, Yee SW, Stein CM, Carrillo M, Evans WE, Klein TE . 6 . Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing . Clinical Pharmacology and Therapeutics . 89 . 3 . 387–91 . March 2011 . 21270794 . 3098761 . 10.1038/clpt.2010.320 .
  26. Book: Mutschler E, Schäfer-Korting M . Arzneimittelwirkungen. 107, 936. de. Stuttgart. Wissenschaftliche Verlagsgesellschaft. 2001. 8th. 978-3-8047-1763-3.
  27. Payne K, Newman W, Fargher E, Tricker K, Bruce IN, Ollier WE . TPMT testing in rheumatology: any better than routine monitoring? . Rheumatology . 46 . 5 . 727–9 . May 2007 . 17255139 . 10.1093/rheumatology/kel427 . free .
  28. Web site: Label: Mercaptopurine – mercaptopurine tablet. 11 March 2015. live. https://web.archive.org/web/20151006122006/http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=15904472-4c32-4224-95d3-eb131a7ff9c8. 6 October 2015.
  29. Web site: Purixan suspension . DailyMed . 9 April 2019 . 9 April 2020.
  30. Wang L, Pelleymounter L, Weinshilboum R, Johnson JA, Hebert JM, Altman RB, Klein TE . Very important pharmacogene summary: thiopurine S-methyltransferase . Pharmacogenetics and Genomics . 20 . 6 . 401–5 . June 2010 . 20154640 . 3086840 . 10.1097/FPC.0b013e3283352860 .
  31. Web site: Bouton K . The New York Times Magazine . 29 January 1989 . The Nobel Pair . https://web.archive.org/web/20161007121620/http://www.nytimes.com/1989/01/29/magazine/the-nobel-pair.html . 2016-10-07 .
  32. Book: Mukherjee S . 2010 . The Emperor of All Maladies: A Biography of Cancer . New York . Scribner . 91–92 . 978-1439170915.

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Mercaptopurine".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.