Mercaptopurine
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| Systematic (IUPAC) name |
| 3,7-dihydropurine-6-thione |
| Clinical data |
| Trade names |
Purinethol |
| AHFS/Drugs.com |
monograph |
| MedlinePlus |
a682653 |
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Pregnancy
category
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Legal status
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|
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Routes of
administration
|
Oral |
| Pharmacokinetic data |
| Bioavailability |
5 to 37% |
| Metabolism |
xanthine oxidase |
| Half-life |
60 to 120 min., longer for its active metabolites |
| Excretion |
Renal |
| Identifiers |
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CAS Registry Number
|
50-44-2 Y |
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ATC code
|
L01BB02 |
| PubChem |
CID: 667490 |
| IUPHAR/BPS |
7226 |
| DrugBank |
DB01033 Y |
| ChemSpider |
580869 Y |
| UNII |
PKK6MUZ20G Y |
| KEGG |
D04931 Y |
| ChEBI |
CHEBI:50667 Y |
| ChEMBL |
CHEMBL1425 Y |
| Chemical data |
| Formula |
C5H4N4S |
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Molecular mass
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152.177 g/mol |
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InChI
-
InChI=1S/C5H4N4S/c10-5-3-4(7-1-6-3)8-2-9-5/h1-2H,(H2,6,7,8,9,10) Y
Key:GLVAUDGFNGKCSF-UHFFFAOYSA-N Y
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| Y (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]
Contents
- 1 Medical uses
- 2 Mechanisms of action
- 3 Adverse reactions
- 4 Drug interactions
- 5 Precautions
- 6 Synthesis
- 7 See also
- 8 References
- 9 External links
Medical uses
It is used to treat leukemia, non-Hodgkin's lymphoma in children,[citation needed] polycythemia vera,[3] psoriatic arthritis,[4] and inflammatory bowel disease (such as Crohn's disease and ulcerative colitis). Also for some Lupus (SLE) patients. [5] It has demonstrated some in vitro effectiveness against Mycobacterium paratuberculosis.[6]
Mechanisms of action
Official information from the package insert for purinethol:[7]
- 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 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
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 inflammation of the pancreas.
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.
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.[9][10][11] 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.[12] 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 patients are homozygous for these variants.[12][13] However, an assay of TPMT activity in red blood cells or a TPMT genetic test can identify patients with reduced TPMT activity, allowing for the adjustment of mercaptopurine dose or avoidance of the drug entirely.[12][14] The FDA-approved drug label for mercaptopurine recommends testing for TPMT activity to identify patients at risk for myelotoxicity.[15] Indeed, testing for TPMT activity is currently one of the few examples of pharmacogenetics being translated into routine clinical care.[16]
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 6mp helps reduce 6mmp levels, which are toxic to liver tissue, whilst increasing the therapeutic levels of 6mp for some inflammatory conditions.
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.[17] 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.[18]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.[19] 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."[20]
Mercaptopurine causes changes to chromosomes in animals and humans, though a study in 1990[21] found, "while the carcinogenic potential of 6-MP cannot be precluded, it can be only very weak or marginal." Another study in 1999[22] noted an increased risk of developing leukemia when taking large doses of 6-MP with other cytotoxic drugs.
Synthesis
- Step one is malonic ester + urea to give barbituric acid.
Mercaptopurine synthesis:
[23][24] GB 713286 U.S. Patent 2,721,886 U.S. Patent 2,724,711 U.S. Patent 2,933,498 U.S. Patent 267,709
See also
References
- ^ [1]
- ^ 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.
- ^ Shullenberger, C. C. (1962). "Long-rangetreatment of polycythemia vera with 6-mercaptopurine". Cancer chemotherapy reports. Part 1 16: 251–252. PMID 13912387. edit
- ^ 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
- ^ 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.
- ^ 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.
- ^ "PURINETHOL (mercaptopurine) tablet [Gate Pharmaceuticals]" (PDF). DailyMed. Gate Pharmaceuticals. August 2012. Retrieved 31 December 2013.
- ^ Hansen, Barbara. "Purine and Pyrimidine Metabolism." USMLE STEP 1 Biochemistry and Medical Genetics Lecture Notes. 2010 ed. N.p.: Kaplan, 2010. 288-90. Print.
- ^ Zaza G, Cheok M, Krynetskaia N, Thorn C, Stocco G, Hebert JM, McLeod H, Weinshilboum RM, Relling MV, Evans WE, Klein TE, Altman RB (September 2010). "Thiopurine pathway". Pharmcogenet Genomics 20 (9): 573–4. doi:10.1097/FPC.0b013e328334338f. PMID 19952870.
- ^ Stocco G, Pelin M, Franca R, De Iudicibus S, Cuzzoni E, Favretto D, Martelossi S, Ventura A, Decorti G. (April 2014). "Pharmacogenetics of azathioprine in inflammatory bowel disease: a role for glutathione-S-transferase?". World J Gastroenterol 20 (13): 3534–41. doi:10.3748/wjg.v20.i13.3534. PMID 24707136.
- ^ Fujita K, Sasaki Y (August 2007). "Pharmacogenomics in drug-metabolizing enzymes catalyzing anticancer drugs for personalized cancer chemotherapy". Curr. Drug Metab. 8 (6): 554–62. doi:10.2174/138920007781368890. PMID 17691917.
- ^ a b c Relling MV, Gardner EE, Sandborn WJ, Schmiegelow K, Pui CH, Yee SW, Stein CM, Carrillo M, Evans WE, Klein TE; Clinical Pharmacogenetics Implementation Consortium (March 2011). "Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing". Clin Pharmacol Ther 89 (3): 387–91. doi:10.1038/clpt.2010.320. PMC 3098761. PMID 21270794.
- ^ Mutschler, Ernst; Schäfer-Korting, Monika (2001). Arzneimittelwirkungen (in German) (8 ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. pp. 107, 936. ISBN 3-8047-1763-2.
- ^ Payne, K.; Newman, W.; Fargher, E.; Tricker, K.; Bruce, I. N.; Ollier, W. E. R. (2007). "TPMT testing in rheumatology: Any better than routine monitoring?". Rheumatology 46 (5): 727–729. doi:10.1093/rheumatology/kel427. PMID 17255139.
- ^ "Label: Mercaptopurine - mercaptopurine tablet". Retrieved 11 March 2015.
- ^ Wang L, Pelleymounter L, Weinshilboum R, Johnson JA, Hebert JM, Altman RB, Klein TE (June 2010). "Very important pharmacogene summary: thiopurine S-methyltransferase". Pharmacogenet Genomics 20 (6): 401–5. doi:10.1097/FPC.0b013e3283352860. PMC 3086840. PMID 20154640.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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
- ^ 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
- FDA Label, Mercaptopurine (PDF)
