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| Clinical data | |
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| Trade names | Purinethol, Purixan, others |
| Other names | 6-mercaptopurine (6-MP) |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a682653 |
| License data | |
| Routes of administration | By mouth |
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| Pharmacokinetic data | |
| Bioavailability | 5 to 37% |
| Metabolism | xanthine oxidase |
| Eliminationhalf-life | 60 to 120 min., longer for its active metabolites |
| Excretion | kidney |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.000.035 |
| Chemical and physical data | |
| Formula | C5H4N4S |
| Molar mass | 152.18 g·mol−1 |
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Mercaptopurine (6-MP), sold under the brand namePurinethol among others, is a medication used forcancer andautoimmune diseases.[2] Specifically it is used to treatacute lymphocytic leukemia (ALL),acute promyelocytic leukemia (APL),Crohn's disease, andulcerative colitis.[2][3] For acute lymphocytic leukemia it is generally used withmethotrexate.[2] It is taken orally.[2]
Common side effects includebone marrow suppression,liver toxicity, vomiting, and loss of appetite.[2] Other serious side effects include an increased risk of future cancer andpancreatitis.[2] Those with a genetic deficiency inthiopurine S-methyltransferase are at higher risk of side effects.[2] Use inpregnancy may harm the baby.[2] Mercaptopurineis in thethiopurine andantimetabolite family of medications.[4][3]
Mercaptopurine was approved for medical use in the United States in 1953.[2] It is on theWorld Health Organization's List of Essential Medicines.[5]
It is used to treatacute lymphocytic leukemia,Crohn's disease, andulcerative colitis.[6]
Some of theadverse reactions of taking mercaptopurine may include diarrhea, nausea, vomiting, loss of appetite, fatigue, stomach/abdominal pain, weakness, skinrash, 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, darkurine, and painful or difficult urination. Other more serious side effects include black or tarrystools (melena), bloody stools, and bloodyurine. 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 includerash,itching,swelling,dizziness, troublebreathing, andinflammation of the pancreas.
In some cases, mercaptopurine maysuppress the production of blood cells, bothwhite blood cells andred blood cells. It may be toxic tobone 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 inthiopurineS-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]
Mercaptopurine can lower the body's ability to fight off infection. Those taking it should get permission from a doctor to receiveimmunizations andvaccinations. It is also recommended that, while on the drug, one should avoid those having recently received oralpolio vaccine.
This drug was formerly not recommended during pregnancy and early evidence indicated pregnant women on the drug (or the relatedazathioprine) 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 tomethotrexate, was ineffective as a single-agentabortifacient; every woman in the mercaptopurine arm of the study had fetal cardiac activity at follow-up (two weeks later) and was given asuction 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 tochromosomes 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 othercytotoxic drugs.
Allopurinol inhibitsxanthine oxidase, the enzyme that breaks down mercaptopurine. Those takingallopurinol (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.
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Official information from the package insert for purinethol:[18]
6-MP ribonucleotide inhibits purine nucleotide synthesis and metabolism by inhibiting an enzyme calledphosphoribosyl pyrophosphate amidotransferase (PRPP amidotransferase). Since this enzyme is the rate limiting factor for purine synthesis,[21] this alters the synthesis and function ofRNA andDNA.[citation needed] Mercaptopurine interferes withnucleotide interconversion and glycoprotein synthesis.
The enzymethiopurineS-methyltransferase (TPMT) is responsible, in part, for the inactivation of 6-mercaptopurine. TPMT catalyzes themethylation of 6-mercaptopurine into the inactive metabolite 6-methylmercaptopurine – thismethylation prevents mercaptopurine from further conversion into active,cytotoxic thioguanine nucleotide (TGN) metabolites.[22][23][24] Certaingenetic variations within the TPMT gene can lead to decreased or absent TPMT enzyme activity, and individuals who arehomozygous orheterozygous for these types ofgenetic 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 arehomozygous for these variants.[25][26] However, an assay of TPMT activity inred blood cells or a TPMTgenetic 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 formyelotoxicity.[28][29] Testing for TPMT activity is an example ofpharmacogenetics being translated into routine clinical care.[30]
6-MP was discovered by Nobel Prize–winning scientistsGertrude B. Elion andGeorge H. Hitchings atBurroughs Wellcome inTuckahoe, New York,[31] and was clinically developed in collaboration with investigators at Memorial Hospital (nowMemorial Sloan Kettering Cancer Center in New York City).[32] The collaboration was initiated byCornelius P. Rhoads, who had runchemical weapons programs for the US Army and had been involved in the work that led to the discovery thatnitrogen mustards could potentially be used as cancer drugs, and had become the director of Memorial in 1948.[32]
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