Mercaptopurine

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Mercaptopurine
Mercaptopurine.svg
Mercaptopurin ball-and-stick.png
Systematic (IUPAC) name
3,7-dihydropurine-6-thione
Clinical data
Trade names Purinethol
AHFS/Drugs.com monograph
MedlinePlus a682653
Pregnancy cat.
  • D
Legal status
  • Prescription only
Routes Oral
Pharmacokinetic data
Bioavailability 5 to 37%
Metabolism xanthine oxidase
Half-life 60 to 120 min., longer for its active metabolites
Excretion Renal
Identifiers
CAS number 50-44-2 YesY
ATC code L01BB02
PubChem CID 667490
DrugBank DB01033
ChemSpider 580869 YesY
UNII PKK6MUZ20G YesY
KEGG D04931 YesY
ChEBI CHEBI:50667 YesY
ChEMBL CHEMBL1425 YesY
Chemical data
Formula C5H4N4S 
Mol. mass 152.177 g/mol
 YesY (what is this?)  (verify)

Mercaptopurine (also called 6-mercaptopurine, 6-MP or its brand name Purinethol[1]) is an immunosuppressive drug. It is a thiopurine.[2]

Uses[edit]

It is used to treat leukemia, pediatric non-Hodgkin's lymphoma,[citation needed] polycythemia vera,[3] psoriatic arthritis,[4] and inflammatory bowel disease (such as Crohn's disease and ulcerative colitis).[5] It has demonstrated some in vitro effectiveness against Mycobacterium paratuberculosis.[6]

Mechanisms of action[edit]

Official information from the package insert for purinethol:[7]

  • Mercaptopurine (6-MP) competes with hypoxanthine and guanine for the enzyme HGPRTase and is itself converted to thioinosinic acid (TIMP).
    • TIMP 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).
  • 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). PRPP Amidotransferase is the rate limiting enzyme of purine synthesis.[8] This alters the synthesis and function of RNA and DNA.[citation needed] Mercaptopurine interferes with nucleotide interconversion and glycoprotein synthesis.

Adverse reactions[edit]

Some of the adverse reactions of taking mercaptopurine will 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.

Symptoms of allergic reaction to mercaptopurine include rash, itching, swelling, dizziness, trouble breathing, and pancreatitis.

Mercaptopurine causes myelosuppression, suppressing the production of white blood cells and red blood cells. It may be toxic to bone marrow. Weekly blood counts are recommended for patients on mercaptopurine. The patient should stop taking the medication at least temporarily if there is an unexplained, abnormally large drop in white blood cell count, or any other blood count.

Patients exhibiting myelosuppression or bone marrow toxicity should be tested for thiopurine methyltransferase (TPMT) enzyme deficiency. Patients with TPMT deficiency are much more likely to develop dangerous myelosuppression.[9] In such patients, it may be possible to continue using mercaptopurine, but at a lower dose.

Drug interactions[edit]

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.

Precautions[edit]

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.[10] 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.[11]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.[12] 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."[13]

Mercaptopurine causes changes to chromosomes in animals and humans, though a study in 1990[14] found, "while the carcinogenic potential of 6-MP cannot be precluded, it can be only very weak or marginal." Another study in 1999[15] noted an increased risk of developing leukemia when taking large doses of 6-MP with other cytotoxic drugs.

Synthesis[edit]

  1. Step one is malonic ester + urea to give barbituric acid.

References[edit]

  1. ^ [1]
  2. ^ Sahasranaman, S.; Howard, D.; Roy, S. (2008). "Clinical pharmacology and pharmacogenetics of thiopurines". European Journal of Clinical Pharmacology 64 (8): 753–767. doi:10.1007/s00228-008-0478-6. PMID 18506437. 
  3. ^ Shullenberger, C. C. (1962). "Long-rangetreatment of polycythemia vera with 6-mercaptopurine". Cancer chemotherapy reports. Part 1 16: 251–252. PMID 13912387.  edit
  4. ^ Baum, J.; Hurd, E.; Lewis, D.; Ferguson, J. L.; Ziff, M. (1973). "Treatment of psoriatic arthritis with 6-mercaptopurine". Arthritis & Rheumatism 16 (2): 139. doi:10.1002/art.1780160202.  edit
  5. ^ Nielsen OH, Vainer B, Rask-Madsen J (November 2001). "Review article: the treatment of inflammatory bowel disease with 6-mercaptopurine or azathioprine". Aliment. Pharmacol. Ther. 15 (11): 1699–708. doi:10.1046/j.1365-2036.2001.01102.x. PMID 11683683. 
  6. ^ Shin SJ, Collins MT (February 2008). "Thiopurine drugs azathioprine and 6-mercaptopurine inhibit Mycobacterium paratuberculosis growth in vitro". Antimicrob. Agents Chemother. 52 (2): 418–26. doi:10.1128/AAC.00678-07. PMC 2224720. PMID 18070971. 
  7. ^ "PURINETHOL (mercaptopurine) tablet [Gate Pharmaceuticals]" (PDF). DailyMed. Gate Pharmaceuticals. August 2012. Retrieved 31 December 2013. 
  8. ^ Hansen, Barbara. "Purine and Pyrimidine Metabolism." USMLE STEP 1 Biochemistry and Medical Genetics Lecture Notes. 2010 ed. N.p.: Kaplan, 2010. 288-90. Print.
  9. ^ Yates, C. R.; Krynetski, E. Y.; Loennechen, T.; Fessing, M. Y.; Tai, H. L.; Pui, C. H.; Relling, M. V.; Evans, W. E. (1997). "Molecular diagnosis of thiopurine S-methyltransferase deficiency: Genetic basis for azathioprine and mercaptopurine intolerance". Annals of internal medicine 126 (8): 608–614. doi:10.7326/0003-4819-126-8-199704150-00003. PMID 9103127. 
  10. ^ Nørgård, B.; L. Pedersen; K. Fonager; S. Rasmussen; H. Sørensen (March 2003). "Azathioprine, mercaptopurine and birth outcome: a population-based cohort study". Alimentary pharmacology and therapeutics 17 (6): 827–834. doi:10.1046/j.1365-2036.2003.01537.x. PMID 12641505. 
  11. ^ Davis, Anne R.; Leslie Miller; Hisham Tamimi; Allen Gown (June 1999). "Methotrexate Compared With Mercaptopurine for Early Induced Abortion". Obstetrics & Gynecology 93 (6): 904–9. doi:10.1016/S0029-7844(98)00569-9. PMID 10362152. 
  12. ^ Coelho, J.; L. Beaugerie, J.F. Colombel, X. Hébuterne, E. Lerebours, M. Lémann, P. Baumer, et al. (February 2011). "Pregnancy outcome in patients with inflammatory bowel disease treated with thiopurines: cohort from the CESAME Study". Gut 60 (2): 198–203. doi:10.1136/gut.2010.222893. PMID 21115547. 
  13. ^ Van Assche, G.; A. Dignass, W. Reinisch, C.J. van der Woude, A. Sturm, M. De Vos, M. Guslandi, et al. (February 2010). "The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Special situations". Journal of Crohn's and Colitis 4 (1): 63–101. doi:10.1016/j.crohns.2009.09.009. PMID 21122490. 
  14. ^ Maekawa, A.; T. Nagaoka, H. Onodera, Y. Matsushima, A. Todate, M. Shibutani, H. Ogasawara, Y. Kodama and Y. Hayashi (May 1990). "Two-year carcinogenicity study of 6-mercaptopurine in F344 rats". Journal of Cancer Research and Clinical Oncology 116 (3): 245–250. doi:10.1007/BF01612898. PMID 2370249. 
  15. ^ Bo J, Schrøder H, Kristinsson J, Madsen B, Szumlanski C, Weinshilboum R, Andersen JB, Schmiegelow K (September 1999). "Possible carcinogenic effect of 6-mercaptopurine on bone marrow stem cells: relation to thiopurine metabolism". Cancer 86 (6): 1080–6. doi:10.1002/(SICI)1097-0142(19990915)86:6<1080::AID-CNCR26>3.0.CO;2-5. PMID 10491537. 
  16. ^ Elion, G. B.; Burgi, E.; Hitchings, G. H. (1952). "Studies on Condensed Pyrimidine Systems. IX. The Synthesis of Some 6-Substituted Purines". Journal of the American Chemical Society 74 (2): 411. doi:10.1021/ja01122a037.  edit
  17. ^ Beaman, A. G.; Robins, R. K. (1961). "Potential Purine Antagonists. XXVII. Synthesis and Reactions of Some Purinesulfonyl Fluorides1". Journal of the American Chemical Society 83 (19): 4038. doi:10.1021/ja01480a021.  edit

External links[edit]