6-メルカプトプリン 6-mercaptopurine 6MP Purinethol
出典(authority):フリー百科事典『ウィキペディア(Wikipedia)』「2016/05/20 03:50:43」(JST)
Systematic (IUPAC) name | |
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3,7-dihydropurine-6-thione
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Clinical data | |
Trade names | Purinethol |
AHFS/Drugs.com | monograph |
MedlinePlus | a682653 |
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Routes of administration |
Oral |
Legal status | |
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Pharmacokinetic data | |
Bioavailability | 5 to 37% |
Metabolism | xanthine oxidase |
Biological half-life | 60 to 120 min., longer for its active metabolites |
Excretion | Kidney |
Identifiers | |
CAS Number | 50-44-2 Y |
ATC code | L01BB02 (WHO) |
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 |
Molar mass | 152.177 g/mol |
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Mercaptopurine (also called 6-mercaptopurine, 6-MP or its brand name Purinethol[1]) is an immunosuppressive medication. It is used to treat acute lymphocytic leukemia, Crohn's disease, and ulcerative colitis.[2] It is a thiopurine.[3]
It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.[4]
It is used to treat acute lymphocytic leukemia, Crohn's disease, and ulcerative colitis.[2]
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.
Toxicity of mercaptopurine can be linked to genetic polymorphisms in thiopurine S-methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA). Patients with specific allele variants will require dose adjustments. Caucasian patients with a variant allele of the ITPA gene, experience higher rates of febrile neuropenia than patients of other ethnic groups, due to differences in allelic frequencies among ethnicities.[5]
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.[6] 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.[7] 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.[8] 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."[9]
Mercaptopurine causes changes to chromosomes in animals and humans, though a study in 1990[10] found, "while the carcinogenic potential of 6-MP cannot be precluded, it can be only very weak or marginal." Another study in 1999[11] noted an increased risk of developing leukemia when taking large doses of 6-MP with other cytotoxic drugs.
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.
This section may be too technical for most readers to understand. Please help improve this section to make it understandable to non-experts, without removing the technical details. The talk page may contain suggestions. (December 2014) |
Official information from the package insert for purinethol:[12]
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.[13] This alters the synthesis and function of RNA and DNA.[citation needed] Mercaptopurine interferes with nucleotide interconversion and glycoprotein synthesis.
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.[14][15][16] 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.[17] 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.[17][18] 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.[17][19] The FDA-approved drug label for mercaptopurine recommends testing for TPMT activity to identify patients at risk for myelotoxicity.[20] Indeed, testing for TPMT activity is currently one of the few examples of pharmacogenetics being translated into routine clinical care.[21]
6 MP was discovered by Nobel Prize winning scientists Gertrude B. Elion and George H. Hitchings at Burroughs Wellcome in Tuckahoe, New York,[22] and was clinically developed in collaboration with investigators at Memorial Hospital (now Memorial Sloan Kettering Cancer Center in New York City.[23] 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.[23]
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リンク元 | 「6-メルカプトプリン」「拒絶反応」「代謝拮抗薬」 |
関連記事 | 「MP」「M」「mp」 |
反応時期 | 原因 | 治療 | |||
超急性拒絶反応 | 24時間以内 | 体液性 | レシピエントの抗HLA抗体 | 移植臓器の摘出 | 免疫抑制薬無効 |
急性拒絶反応 | 1週間後~3ヶ月後 | 細胞性 | レシピエントの抗原提示細胞によるドナー抗原提示? | 免疫抑制薬有効 | |
慢性拒絶反応 | 3ヶ月後~ | 体液性 | 再移植 | 免疫抑制薬無効 | |
免疫抑制薬(シクロスポリン、タクロリムス、6-MP、アザチオプリン) |
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