Azathioprine is used to prevent rejections of kidney or liverallografts, usually in conjunction with other therapies, includingcorticosteroids, other immunosuppressants, and localradiation therapy.[14][15] The administration protocol starts either at the time of transplantation or within the following two days.[13]
Being adisease-modifying antirheumatic drug (DMARD), azathioprine has been used for the management of the signs and symptoms of adult rheumatoid arthritis.[16]Nonsteroidal anti-inflammatory drugs and corticosteroids may be combined or continued (if they were already in use) with azathioprine, but the combination with other DMARDs is not recommended.[13]
Azathioprine has been used in the management of moderate to severe chronically active Crohn's disease,[17] to maintainclinical remission (absence of disease activity) in corticosteroid-dependent patients,[18] and to provide benefit in people withfistulizing Crohn's disease.[19] The onset of action is slow, and several months may be required to achieve a clinical response.[17]
Azathioprine treatment is associated with an increased risk oflymphoma, but whether this is due to the drug or a predisposition related to Crohn's disease is unclear.[20] Lower doses of azathioprine are used as a therapy in children with refractory or corticosteroid-dependent Crohn's disease, without causing many side effects.[21] It may also be used to prevent flares in those withulcerative colitis.[22][needs update]
Azathioprine is sometimes used in systemic lupus erythematosus, requiring a maintenance dose of 15 mg or higher ofprednisone in those who experience recurrent flares.[23]
It is used as an add-on therapy when steroid therapy is given by mouth for pemphigus and myasthenia gravis, as a "steroid-sparing" agent.[11][24][25] Azathioprine is also used to maintain remission in people who havegranulomatosis with polyangiitis.[6]
It can be very effective in eczema and atopic dermatitis, though it is not commonly used.[11] The BritishNational Eczema Society lists it as athird-line treatment for severe to moderate cases of these skin diseases.[26]
It was widely used to treat multiple sclerosis until the first half of the 1990s. Concerns about increased risk ofmalignancy have led to a decreased use, yet it is still used in maintenance treatment for people who frequentlyrelapse.[27] A 2007 Cochrane review found that azathioprine reduced the number of relapses in the first year of treatment and disease progression in the first two to three years and did not find an increase in cancer, and noted the need for direct comparison of azathioprine andinterferon beta, conflicting conclusions regarding cancer, and the potential for long-term risks.[28]
A widely used therapy foridiopathic pulmonary fibrosis was azathioprine in combination with prednisone andN-acetylcysteine. A 2012 study showed that this combination produced worse outcomes than a placebo.[29]
Nausea and vomiting are common adverse effects, especially at the beginning of treatment. Such cases are met with taking azathioprine after meals or transientintravenous administration. Side effects that are probablyhypersensitivity reactions include dizziness, diarrhea,fatigue, andrashes. Hair loss is often seen in transplant patients receiving the drug but rarely occurs under other indications. Because azathioprinesuppresses the bone marrow, patients can developanaemia and be more susceptible toinfection; regular monitoring of theblood count is recommended during treatment.[13][30]Acute pancreatitis can also occur, especially in patients with Crohn's disease.[31] 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 ion-exchange LC-MS (liquid chromotography – 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.[32]
The enzymethiopurine S-methyltransferase (TPMT) is responsible for various activation and deactivation steps in azathioprine's mechanism of action.[34] The first metabolic step that azathioprine undergoes in the body is the conversion to6-mercaptopurine (6-MP; seePharmacokinetics), which is itself animmunosuppressantprodrug.[35][36] The TPMT enzyme is responsible, in part, for themethylation of 6-MP into the inactive metabolite 6-methylmercaptopurine – thismethylation prevents 6-MP from further conversion into active,cytotoxic thioguanine nucleotide (TGN) metabolites.[35][37] Certaingenetic variations within theTPMT 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 azathioprine.[38] 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 arehomozygous for these variants.[38][39] However, an assay of TPMT activity inred blood cells or aTPMTgenetic test can identify patients with reduced TPMT enzyme activity, allowing for the adjustment of azathioprine dose or avoidance of the drug entirely.[38][40] The FDA-approved drug label for azathioprine recommends testing for TPMT activity to identify patients at risk formyelotoxicity.[41] Indeed, testing for TPMT activity is one of the few examples ofpharmacogenetics being translated into routine clinical care.[42] Missense SNP inNUDT15 (e.g., rs116855232, inducing R139C)) has been identified to be a causal factor for AZA-induced leukopenia through a genome-wide association study (GWAS) in East Asians.[43]
Azathioprine is listed as a human carcinogen in the 12th Report on Carcinogens by theNational Toxicology Program ofU.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."[44] Since August 2009, the U.S. FDA has required warnings to be placed on packaging with respect to increased risks of certain cancers.[45]
The risks involved seem to be related both to the duration and the dosage used. People who have previously been treated with analkylating agent may have an excessive risk of cancers if treated with azathioprine. Epidemiological studies byInternational Agency for Research on Cancer have provided "sufficient" evidence of azathioprine carcinogenicity in humans (group 1),[46] although the methodology of past studies and the possible underlying mechanisms are questioned.[47]
Cases ofhepatosplenic T-cell lymphoma – a rare type oflymphoma – 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.[48] 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.[49]
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.[50] Azathioprine causes the accumulation of6-thioguanine (6-TG) in patients' DNA, which might trigger cancer when the patient is later exposed toultraviolet light. Patients taking azathioprine were found to be abnormally sensitive to UVA light.[51]
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. The main symptoms of long-term overdosing are infections of unclear origin,mouth ulcers, and spontaneous bleeding, all of which are consequences of its bone-marrow suppression.[30]
Other purine analogues, such asallopurinol, inhibitxanthine oxidase, the enzyme that breaks down azathioprine, thus increasing the toxicity of azathioprine.[52] Low doses of allopurinol, though, have been shown to safely enhance the efficacy of azathioprine, especially in inflammatory bowel disease nonresponders.[53][54][55] This may still lead to lower lymphocyte counts and higher rates of infection, so the combination requires careful monitoring.[56][57]
Azathioprine decreases the effects of theanticoagulantwarfarin and ofnondepolarizing muscle relaxants, but increases the effect ofdepolarizing muscle relaxants.[30] It can also interfere withniacin (vitamin B3), resulting in at least one case topellagra and fatal medullary aplasia.[58]
Azathioprine can cause birth defects.[59][60][61] 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 inmiscarriage.[62] Birth defects in a child whose father was taking azathioprine have also been reported.[63] Although no adequate andwell-controlled studies have taken place in humans, when given toanimals in doses equivalent to human dosages, teratogenesis was observed.[64] Transplant patients already on this drug should not discontinue on becoming pregnant. This contrasts with the later-developed drugstacrolimus and mycophenolate, which are contraindicated during pregnancy.[59]
Traditionally, as for allcytotoxic drugs, the manufacturer advises not to breastfeed whilst taking azathioprine, but the "lactation risk category" reported by Thomas Hale in his bookMedications and Mothers' Milk lists azathioprine as "L3", termed "moderately safe".[65]
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 1–2 hours, and the average plasma half-life is 26 to 80 minutes for azathioprine and 3–5 hours for drug plus metabolites; 20 to 30% are bound toplasma proteins while circulating in the bloodstream.[11][30][68][69]
Azathioprine is aprodrug, 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) byreductive cleavage of thethioether (–S–). This is mediated byglutathione 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 thiodeoxyguanosine triphosphate (TdGTP) viathioinosine monophosphate (TIMP) and several further intermediates. On a second path, the sulfur atom of 6-MP and TIMP ismethylated. The end products of azathioprine metabolism arethiouric acid (38%) and various methylated andhydroxylated purines, which are excreted via the urine.[39][68][69]
Azathioprine inhibitspurine synthesis. Purines are needed to produce DNA and RNA. By inhibiting purine synthesis, less DNA and RNA are produced for the synthesis ofwhite blood cells, thus causing immunosuppression.
Azathioprine is converted within tissues to 6-MP, some of which is converted, in turn, to6-thioguanine by the addition of an amino group. Both 6-MP and 6-thioguanine are conjugated withribose and then phosphorylated to form thenucleotidesthioinosinic acid and thioguanylic acid, respectively.[12] These nucleotides masquerade, respectively, asinosinic acid andguanylic acid; the former is the starting point for purine nucleotide biosynthesis, while the latter is one of the building blocks of DNA and RNA.
The nucleotides are incorporated into newly synthesized (but nonfunctional) DNA, haltingreplication.
The nucleotides act to inhibit glutamine-phosphoribosyl pyrophosphate amidotransferase (GPAT), one of the enzymes involved inpurine biosynthesis, one of the earlier steps in the synthesis of DNA and RNA. They achieve GPAT inhibition through a form of negative feedback calledproduct inhibition.[70] Because actively replicating cells (such as cancer cells and theT cells andB cells of theimmune system) are most active in synthesizing purine, making new DNA, these cells are most strongly affected.[71][11]
A portion of the nucleotides is additionally phosphorylated to the triphosphate forms. These bind toGTP-binding proteinRac1, blocking synthesis of the proteinBcl-xL, thus sending activated T cells andmononuclear cells intoapoptosis (programmed cell death). Increased apoptosis of mononuclear cells is seen in inflammatory bowel disease patients treated with azathioprine.[71]
Azathioprine is athiopurine linked to a secondheterocycle (animidazole derivative) via athioether. 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 inlipophilic solvents such as chloroform, ethanol, and diethyl ether. It dissolves in alkaline aqueous solutions, where ithydrolyzes to 6-MP.[68]
Robert Schwartz investigated the effect of 6-MP on the immune response in 1958 and discovered that it profoundly suppresses the formation ofantibodies when given to rabbits together withantigens.[77] Following the work done by SirPeter Medawar and Gertrude Elion in discovering the immunological basis ofrejection of transplanted tissues and organs, and Schwartz's researches on 6-MP, SirRoy Calne, the British pioneer in transplantation, introduced 6-MP as an experimental immunosuppressant forkidney andheart transplants.[78] 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.[74][11]
In April 1962, with regimens consisting of azathioprine and prednisone, the transplantation of kidneys to unrelated recipients (allotransplantation) was successful for the first time.[11][79] For many years, this kind of dual therapy with azathioprine andglucocorticoids was the standard antirejection regimen, until cyclosporin was introduced into clinical practice (by Calne as well) in 1978.
Cyclosporin has now replaced some of the azathioprine use due to a longer survival time, especially in heart-related transplantations.[80][81][82] 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, feweropportunistic infections, and a lower incidence of acute rejection.[15][83]
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