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- an immunosuppressive drug (trade name Imuran) used to prevent rejection of a transplanted organ (同)Imuran
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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/03/24 12:03:54」(JST)
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| Systematic (IUPAC) name | |
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6-[(1-Methyl-4-nitro-1H-imidazol-5-yl)sulfanyl]-7H-purine
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| Clinical data | |
| Pronunciation | /ˌæzəˈθaɪəˌpriːn/[3] |
| Trade names | Azasan, Imuran and others |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a682167 |
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| Routes of administration |
Mainly oral (sometimes initially intravenous) |
| Legal status | |
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| Pharmacokinetic data | |
| Bioavailability | 60±31% |
| Protein binding | 20–30% |
| Metabolism | Activated non-enzymatically, deactivated mainly by xanthine oxidase |
| Biological half-life | 26–80 minutes (azathioprine) 3–5 hours (drug plus metabolites) |
| Excretion | Renal, 98% as metabolites |
| Identifiers | |
| CAS Number | 446-86-6 Y 55774-33-9 (sodium salt) |
| ATC code | L04AX01 (WHO) |
| PubChem | CID 2265 |
| DrugBank | DB00993 Y |
| ChemSpider | 2178 Y |
| UNII | MRK240IY2L Y |
| KEGG | D00238 Y |
| ChEBI | CHEBI:2948 Y |
| ChEMBL | CHEMBL1542 Y |
| Chemical data | |
| Formula | C9H7N7O2S |
| Molar mass | 277.263 g/mol |
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| Physical data | |
| Melting point | 238 to 245 °C (460 to 473 °F) |
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Azathioprine (AZA), also known by its brand name Imuran, is an immunosuppressive drug used in organ transplantation and autoimmune diseases and belongs to the chemical class of purine analogues.[1] Synthesized originally as a cancer drug and a prodrug for mercaptopurine in 1957, it has been widely used as an immunosuppressant for more than 50 years.[4]
Azathioprine acts as a prodrug for mercaptopurine, inhibiting an enzyme required for the synthesis of DNA. Thus, it most strongly affects proliferating cells, such as the T cells and B cells of the immune system.[5][6]
The main adverse effect of azathioprine is bone marrow suppression, which can be life-threatening, especially in people with a genetic deficiency of the enzyme thiopurine S-methyltransferase.[7] It is also listed by the International Agency for Research on Cancer as a group 1 carcinogen (carcinogenic to humans).[2]
Azathioprine is produced by a number of manufacturers under different brand names. It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[8]
Contents
- 1 Medical uses
- 1.1 Transplantation
- 1.2 Rheumatoid arthritis
- 1.3 Crohn's disease
- 1.4 Others
- 2 Adverse effects
- 2.1 Pharmacogenetics
- 2.2 Cancers
- 2.2.1 Skin cancers
- 2.3 Drug interactions
- 3 Overdose
- 4 Pregnancy and breastfeeding
- 5 Pharmacokinetics
- 6 Mechanism of action
- 7 Physical and chemical properties
- 8 History
- 9 References
- 10 External links
Medical uses
Azathioprine is used alone or in combination with other immunosuppressive therapy to prevent rejection following organ transplantation, and to treat an array of autoimmune diseases, including rheumatoid arthritis, pemphigus, systemic lupus erythematosus, Behçet's disease, and other forms of vasculitis, autoimmune hepatitis, atopic dermatitis, myasthenia gravis, neuromyelitis optica (Devic's disease), restrictive lung disease, and others.[6] It is also an important therapy and steroid-sparing agent for inflammatory bowel disease (such as Crohn's disease and ulcerative colitis) and for multiple sclerosis.[7]
In the United States, it is currently approved by the Food and Drug Administration (FDA) for use in kidney transplantation from human donors, and for rheumatoid arthritis.[1]
Transplantation
Azathioprine is used to prevent rejections of kidney or liver allografts, usually in conjunction with other therapies including corticosteroids, other immunosuppressants, and local radiation therapy.[9][10] The administration protocol starts either at the time of transplantation or within the following two days.[1]
Rheumatoid arthritis
Being a disease-modifying antirheumatic drug (DMARD), azathioprine has been used for the management of the signs and symptoms of adult rheumatoid arthritis.[11] Nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids may be combined or continued (if they were already in use) with azathioprine, but the combination with other DMARDs is not recommended.[1]
Crohn's disease
Azathioprine has been used in the management of moderately to severely or chronically active Crohn's disease,[12] to maintain clinical remission (absence of disease activity) in corticosteroid-dependent patients,[13] and to provide benefit in people with fistulizing Crohn's disease.[14] The onset of action is slow and it may require several months to achieve clinical response.[12]
Azathioprine treatment is associated with an increased risk of lymphoma, but it is unclear if this is due to the drug or a predisposition related to Crohn's disease.[15] Lower doses of azathioprine are used as a therapy in children with refractory or corticosteroid-dependent Crohn's disease, without causing many side effects.[16]
In Crohn’s disease, treatment with azathioprine shortly after diagnosis was no more likely to result in corticosteroid-free remission than standard care or placebo.[17]
Others
Azathioprine is sometimes used in systemic lupus erythematosus patients who require a maintenance dose of 15 mg or higher of prednisone and those who experience recurrent flares.[18]
It is used as an adjuvant in the oral steroid therapy of pemphigus and myasthenia gravis, as a "steroid-sparing" agent for reducing the dose of cortisteroids.[6][19][20]
It was shown to be very effective in eczema and atopic dermatitis in researches, even though it is not commonly used.[6] The British National Eczema Society lists it as a third-line treatment for severe to moderate cases of these skin diseases.[21]
It was widely used for the treatment of multiple sclerosis until the first half of the 1990s. Concerns about increased risk of malignancy has led to a decreased use, yet it is still used in maintenance treatment for patients who frequently relapse.[22]
Adverse effects
An example of azathioprine 50-mg oral tablets
Nausea and vomiting are common adverse effects, especially at the beginning of a treatment. Such cases are met with taking azathioprine after meals or transient intravenous administration. Side effects that are probably hypersensitivity reactions include dizziness, diarrhea, fatigue, and skin rashes. Hair loss is often seen in transplant patients receiving the drug, but rarely occurs under other indications. Because azathioprine suppresses the bone marrow, patients can develop anaemia and will be more susceptible to infection; regular monitoring of the blood count is recommended during treatment.[1][23] Acute pancreatitis can also occur, especially in patients with Crohn's disease.[24]
Under FDA rules, like many other immunosuppressants, the use of this drug excludes eligibility for blood donation.[25]
Pharmacogenetics
The enzyme thiopurine S-methyltransferase (TPMT) is responsible for various activation and deactivation steps in azathioprine's mechanism of action. The first metabolic step that azathioprine undergoes in the body is the conversion to 6-mercaptopurine (6-MP; see Pharmacokinetics), which is itself an immunosuppressant prodrug.[26][27] The TPMT enzyme is responsible, in part, for the methylation of 6-MP into the inactive metabolite 6-methylmercaptopurine - this methylation prevents 6-MP from further conversion into active, cytotoxic thioguanine nucleotide (TGN) metabolites.[26][28] 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 azathioprine.[29] 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.[29][30] 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 azathioprine dose or avoidance of the drug entirely.[29][31] The FDA-approved drug label for azathioprine recommends testing for TPMT activity to identify patients at risk for myelotoxicity.[32] Indeed, testing for TPMT activity is currently one of the few examples of pharmacogenetics being translated into routine clinical care.[33]
Cancers
Azathioprine is listed as a human carcinogen in the 12th Report on Carcinogens by the National Toxicology Program of U.S. Department of Health and Human Services, asserting that it is "known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans."[34] Since August 2009, the U.S. Food and Drug Administration has required warnings to be placed on packaging with respect to increased risks of certain cancers.[35]
The risks involved seem to be related both to the duration and to the dosage used. People who have previously been treated with an alkylating agent may have an excessive risk of cancers if treated with azathioprine. Epidemiological studies by International Agency for Research on Cancer (IARC) have provided "sufficient" evidence of azathioprine carcinogenicity in humans (Group 1),[36] although the methodology of past studies and the possible underlying mechanisms are questioned.[37]
The various diseases requiring transplantation may in themselves increase the risks of non-Hodgkin's lymphoma, squamous cell carcinomas of the skin, hepatobiliary carcinomas, and mesenchymal tumours to which azathioprine may add additional risks. Those receiving azathioprine for rheumatoid arthritis may have a lower risk than those undergoing transplantation.[2]
Cases of hepatosplenic T-cell lymphoma – a rare type of lymphoma – have been reported in patients treated with azathioprine. The majority occurred in patients with inflammatory bowel disease. Adolescents and young adult males were the majority of cases.[38] They presented with a very aggressive disease course and, with one exception, died of the lymphoma. The FDA has required changes to the labeling to inform users and clinicians of the issue.[39]
Skin cancers
In transplant patients, skin cancer is 50 to 250 times more common than in the general population, and between 60% and 90% of patients are affected 20 years after transplantation. The use of immunosuppressive medication including azathioprine in organ transplantation has been linked to increased rates of developing skin cancer.[40] Azathioprine causes the accumulation of 6-thioguanine (6-TG) in patients' DNA, which might trigger cancer when the patient is later exposed to ultraviolet light. Patients taking azathioprine were found to be abnormally sensitive to UVA light.[41]
Drug interactions
Other purine analogues such as allopurinol inhibit xanthine oxidase, the enzyme that breaks down azathioprine, thus increasing the toxicity of azathioprine.[42] On the other hand, low doses of allopurinol have been shown to safely enhance the efficacy of azathioprine, especially in inflammatory bowel disease non-responders.[43][44][45] This may still lead to lower lymphocyte counts and higher rates of infection, therefore the combination requires careful monitoring.[46][47]
Azathioprine decreases the effects of the anticoagulant warfarin and of non-depolarizing muscle relaxants, but increases the effect of depolarizing muscle relaxants.[23] It can also interfere with niacin (vitamin B3), resulting in at least one case to pellagra and fatal medullary aplasia.[48] It has also been reported to cause vitamin B12 deficiency.[49]
Overdose
Large single doses are generally well tolerated; a patient who took 7.5 g azathioprine (150 tablets) at once showed no relevant symptoms apart from vomiting, slightly decreased white blood cell count and marginal changes in liver function parameters. Main symptoms of long-term overdosing are infections of unclear origin, mouth ulcers and spontaneous bleeding, all of which are consequences of the bone marrow suppression.[23]
Pregnancy and breastfeeding
Azathioprine can cause birth defects.[50][51][52] A 2003 population-based study in Denmark showed that the use of azathioprine and related mercaptopurine resulted in a seven-fold incidence of fetal abnormalities as well as a 20-fold increase in miscarriage.[53] Birth defects in a child whose father was taking azathioprine have also been reported.[54] Although no adequate and well-controlled studies have taken place in humans, when given to animals in doses equivalent to human dosages, teratogenesis was observed.[55] Transplant patients already on this drug should not discontinue on becoming pregnant. This contrasts with the later-developed drugs tacrolimus and mycophenolate, which are contraindicated during pregnancy.[50]
Traditionally, as for all cytotoxic drugs, the manufacturer advises not to breastfeed whilst taking azathioprine. However, the "Lactation Risk Category" reported by Thomas Hale in his book "Medications and Mothers' Milk" lists azathioprine as "L3", termed "moderately safe".[56]
Pharmacokinetics
Metabolic pathway for azathioprine (AZA).[57][58] Active metabolites are highlighted.
- XO: xanthine oxidase
- 6-MP: 6-mercaptopurine
- TPMT: thiopurine methyltransferase
- 6-MMP: 6-methylmercaptopurine
- HPRT: hypoxanthine-guanine phosphoribosyltransferase
- TIMP: thioinosine monophosphate, thioinosinic acid
- MeTIMP: methyl-thioinosine monophosphate
- TGTP: thioguanosine triphosphate
- TdGTP: thio-deoxyguanosine triphosphate
Azathioprine is absorbed from the gut to about 88%. Bioavailability varies greatly between individual patients, between 30 and 90%, because the drug is partly inactivated in the liver. Highest blood plasma concentrations, counting not only the drug itself but also its metabolites, are reached after one to two hours; and the average plasma half-life is 26 to 80 minutes for azathioprine and three to five hours for drug plus metabolites. 20 to 30% are bound to plasma proteins while circulating in the bloodstream.[6][23][59][60]
Azathioprine is a prodrug, a substance that is not an active drug itself but is activated in the body. This happens in several steps; at first it is slowly and almost completely converted to 6-mercaptopurine (6-MP) by reductive cleavage of the thioether (–S–). This is mediated by glutathione and similar compounds in the intestinal wall, the liver and on red blood cells, without the aid of enzymes. 6-MP is metabolized analogously to natural purines, giving thioguanosine triphosphate (TGTP) and thio-deoxyguanosine triphosphate (TdGTP) via thioinosine monophosphate (TIMP) and several further intermediates. On a second path, the sulfur atom of 6-MP and TIMP is methylated. The end products of azathioprine metabolism are thiouric acid (38%) and various methylated and hydroxylated purines, which are excreted via the urine.[30][59][60]
Mechanism of action
| 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) |
The purine molecule is the framework for two of the four bases that occur in DNA, adenine and guanine. Consequently, blocking the synthesis of purine also hinders DNA synthesis and thus inhibits the proliferation of cells, especially fast-growing cells without a method of nucleotide salvage ("recycling"), such as lymphocytes.[5][60] Two types of lymphocytes, T cells and B cells, are particularly affected by the inhibition of purine synthesis.[42]
Azathioprine's active metabolite methyl-thioinosine monophosphate (MeTIMP) is a purine synthesis inhibitor that works by blocking the enzyme amidophosphoribosyltransferase,[61] possibly among others. Additional mechanisms, mediated by other metabolites, have been discovered several decades after the drug's introduction, mainly in the 1990s and 2000s:[5] Thioguanosine triphosphate (TGTP) is incorporated into RNA, compromising its functionality. It also interacts with the GTP-binding protein Rac1, blocking upregulation of the protein Bcl-xL and thus sending activated T cells into apoptosis (a kind of programmed cell death). The closely related thio-deoxyguanosine triphosphate (TdGTP) is built into DNA.[58][61] Thioinosinic acid impedes later steps of DNA synthesis via enzymes such as adenylosuccinate synthase and IMP dehydrogenase. Moreover, azathioprine blocks the downstream effects of CD28 costimulation, a process required for T cell activation.[62][verification needed] In vivo data indicate inflammatory bowel disease patients treated with azathioprine have more mononuclear cells that have undergone apoptosis than untreated controls, indicating this mechanism may be responsible for the in vivo response to the drug in this disease.[5]
Physical and chemical properties
Azathioprine is a thiopurine linked to a second heterocycle (an imidazole derivative) via a thioether. It is a pale yellow solid with a slightly bitter taste and a melting point of 238–245 °C. It is practically insoluble in water and only slightly soluble in lipophilic solvents such as chloroform, ethanol and diethylether. It dissolves in alkaline aqueous solutions, where it hydrolyzes to 6-mercaptopurine.[59]
Azathioprine is synthesized from 5-chloro-1-methyl-4-nitro-1H-imidazole and 6-mercaptopurine in dimethyl sulfoxide (DMSO).[63] The synthesis of the former starts with an amide from methylamine and diethyl oxalate, which is then cyclizised and chlorinated with phosphorus pentachloride;[64] the nitro group is introduced with nitric and sulfuric acid.
History
Azathioprine was synthesized by George Herbert Hitchings and Gertrude Elion in 1957 (named BW 57-322) to produce 6-mercaptopurine (6-MP) in a metabolically active but masked form, and at first used as a chemotherapy drug.[4][65][66]
Robert Schwartz investigated the effect of 6-MP on the immune response in 1958 and discovered that it profoundly suppresses the formation of antibodies when given to rabbits together with antigens.[67] Following the work done by Sir Peter Medawar and Gertrude Elion in discovering the immunological basis of rejection of transplanted tissues and organs, and Schwartz's researches on 6-MP, Sir Roy Calne, the British pioneer in transplantation, introduced 6-MP as an experimental immunosuppressant for kidney and heart transplants.[68] When Calne asked Elion for related compounds to investigate, she suggested azathioprine, which was subsequently found out to be superior (as effective and less toxic to the bone marrow) by Calne.[4][6] On 5 April 1962, with regimens consisting of azathioprine and prednisone, the transplantation of kidneys to unrelated recipients (allotransplantation) was successful for the first time.[6][69] For many years, this kind of dual therapy with azathioprine and glucocorticoids was the standard antirejection regimen, until ciclosporin was introduced into clinical practice (by Calne as well) in 1978.
Ciclosporin has now replaced some of the azathioprine use due to a longer survival time, especially in heart-related transplantations.[70][71][72] Moreover, despite being considerably more expensive, mycophenolate mofetil is also increasingly being used in place of azathioprine in organ transplantation, as it is associated with less bone marrow suppression, fewer opportunistic infections, and a lower incidence of acute rejection.[10][73]
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External links
- Imuran
- Azasan (manufacturer's website)
- U.S. National Library of Medicine: Drug Information Portal - Azathioprine
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UpToDate Contents
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- 1. 炎症性腸疾患へのアザチオプリン、メルカプトプリンの投与の概要overview of azathioprine and mercaptopurine use in inflammatory bowel disease [show details]… Thiopurines (ie, azathioprine [AZA] and mercaptopurine, also known as 6-mercaptopurine, [6-MP]) exert a glucocorticoid-sparing effect for patients with inflammatory bowel disease (IBD) who cannot maintain …
- 2. リウマチ性疾患に使用した場合のアザチオプリンの薬理作用および副作用pharmacology and side effects of azathioprine when used in rheumatic diseases [show details]… Azathioprine (AZA) is an immunosuppressive agent that acts through its effects as an antagonist of purine metabolism, resulting in the inhibition of deoxyribonucleic acid (DNA), ribonucleic acid (RNA) …
- 3. 成人における肝移植：免疫抑制の概要liver transplantation in adults overview of immunosuppression [show details]…mycophenolic acid (MPA), a purine synthesis inhibitor, and azathioprine. The original drugs in this class, cyclophosphamide (Cytoxan) and azathioprine (Imuran), are rarely used in transplantation in the United …
- 4. 合併症の発症リスクの高い中等症から重症のクローン病を患う成人患者に行う治療の概要overview of medical management of high risk adult patients with moderate to severe crohn disease [show details]…(eg, azathioprine [AZA], 6-mercaptopurine [6-MP], or methotrexate) . We modify our approach for older patients (age >60 years) and young male patients, and this is discussed below. Azathioprine (AZA) …
- 5. 自己免疫性肝炎：治療autoimmune hepatitis treatment [show details]…mg daily) and azathioprine (50 mg daily) The dose of azathioprine can be increased to 2 mg/kg daily (maximum dose of 200 mg daily) if needed to achieve remission. In Europe, azathioprine at a dose of …
English Journal
- Neuromyelitis optica, atypical hemophagocytic lymphohistiocytosis and heterozygous perforin A91V mutation.
- Palterer B1, Brugnolo F2, Sieni E2, Barilaro A3, Parronchi P4.
- Journal of neuroimmunology.J Neuroimmunol.2017 Oct 15;311:10-13. doi: 10.1016/j.jneuroim.2017.08.003. Epub 2017 Aug 15.
- PMID 28863861
- Common variable immunodeficiency-associated granulomatous and lymphocytic interstitial lung disease successfully treated with a combination regimen of rituximab and azathioprine.
- Moctezuma SI1, Panizo CM2, Landecho MF3.
- Medicina clinica.Med Clin (Barc).2017 Oct 11;149(7):312-313. doi: 10.1016/j.medcli.2017.05.041. Epub 2017 Jul 21.
- PMID 28736065
- Randomised controlled trial of prolonged treatment in the remission phase of ANCA-associated vasculitis.
- Karras A1,2, Pagnoux C3, Haubitz M4, Groot K5, Puechal X6, Tervaert JWC7, Segelmark M8, Guillevin L2,6, Jayne D9; European Vasculitis Society.
- Annals of the rheumatic diseases.Ann Rheum Dis.2017 Oct;76(10):1662-1668. doi: 10.1136/annrheumdis-2017-211123. Epub 2017 May 25.
- PMID 28546260
Japanese Journal
- 稲わら前処理物を用いた並行複発酵微小評価系の構築と効率評価
- Journal of Applied Glycoscience Supplement 2008(0), 72-72, 2008
- NAID 130004626685
- 自己免疫性肝炎について(特別講演,<特集>第68回東京女子医科大学学会総会)
- 東京女子医科大学雑誌 73(5), 126-132, 2003-05-25
- NAID 110007526020
- 膠原病における消化管サイトメガロウィルス感染
- Tokai journal of experimental and clinical medicine 28(1), 35-38, 2003-04
- NAID 110004700348
Related Links
- イムラン錠50mg（一般名：アザチオプリン錠）の薬効分類・副作用・添付文書・薬価などを掲載しています。「処方薬事典」は日経メディカルが ...
- Imuran Tablets 50mg サンドファーマ 3999005F1059 97.5円／錠 処方箋医薬品 警告 臓器移植における本剤の投与は、免疫抑制療法及び移植患者の管理に精通している医師又はその指導のもとで行うこと。 治療抵抗性のリウマチ性疾患に ...
- 「イムラン錠50mg」の用法用量や効能・効果、副作用、注意点を記載しており、添付文書も掲載しています。 イムラン錠50mgの使用上の注意 病気や症状に応じた注意喚起 以下の病気・症状がみられる方は、添付文書の「使用上の注意」等を確認してください
Related Pictures
★リンクテーブル★
| リンク元 | 「アザチオプリン」 |
「アザチオプリン」
- 英
- azathioprine, AZP, AZA, AZ
- ラ
- azathioprinum
- 商
- イムラン Imuran、アザニン
- 関
- GOO. 1414
- 免疫抑制薬
- imidazolyl derivative of 6-mercaptopurine
作用機序
- 体内で6-mercaptopurineに代謝される
- プリン合成を阻害
薬理作用
- 免疫抑制
副作用
- 発熱、悪心、軽度の白血球減少症、血小板減少症
- (まれ)再生不良貧血
- 肝細胞壊死、胆汁分泌停止
適応
- 臓器移植、SLE、関節リウマチ、クローン病、全身性炎症