Editing Azathioprine

{{Short description|Immunosuppressive medication}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Infobox drug
| Watchedfields = changed
| verifiedrevid = 458437709
| drug_name =
| image = Azathioprine.svg
| image_class = skin-invert-image
| width = 125
| alt = 
| image2 = Azathioprine xtal 1984.png
| width2 = 200
| alt2 = 
| caption =

<!-- Clinical data -->
| pronounce = {{IPAc-en|ˌ|æ|z|ə|ˈ|θ|aɪ|ə|ˌ|p|r|iː|n}}{{refn|{{MerriamWebsterDictionary|Azathioprine}}}}
| tradename = Azasan, Imuran, Jayempi, others
| Drugs.com = {{drugs.com|monograph|azathioprine}}
| MedlinePlus = a682167
| licence_EU = 
| DailyMedID = Azathioprine
| licence_US = 
| pregnancy_AU = D
| pregnancy_AU_comment = 
| pregnancy_category = 
| routes_of_administration = [[By mouth]], [[Intravenous therapy|intravenous]]
| class = 
| ATCvet = 
| ATC_prefix = L04
| ATC_suffix = AX01
| ATC_supplemental =

<!-- Legal status -->
| legal_AU = S4
| legal_AU_comment = 
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->
| legal_BR_comment = 
| legal_CA = Rx-only
| legal_CA_comment = 
| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment = 
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment = 
| legal_UK = POM
| legal_UK_comment = 
| legal_US = Rx-only
| legal_US_comment = 
| legal_EU = Rx-only
| legal_EU_comment = <ref name="Jayempi EPAR">{{cite web | title=Jayempi EPAR | website=European Medicines Agency | date=20 April 2021 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/jayempi | access-date=4 March 2023}}</ref><ref>{{cite web | title=Jayempi Product information | website=Union Register of medicinal products | url=https://ec.europa.eu/health/documents/community-register/html/h1557.htm | access-date=3 March 2023}}</ref>
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment = 
| legal_status = <!-- For countries not listed above -->

<!-- Pharmacokinetic data -->
| bioavailability = 60±31%
| protein_bound = 20–30%
| metabolism = Activated non-enzymatically, deactivated mainly by [[xanthine oxidase]]
| metabolites = 
| onset = 
| elimination_half-life= 26–80 minutes (azathioprine)<br />3–5 hours (drug plus metabolites)
| duration_of_action = 
| excretion = [[Kidney]], 98% as metabolites

<!-- Identifiers -->
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number=446-86-6
| CAS_supplemental = <br />{{CAS|55774-33-9}} ([[sodium]] [[salt (chemistry)|salt]])
| PubChem = 2265
| IUPHAR_ligand = 
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00993
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 2178
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = MRK240IY2L
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00238
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 2948
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1542
| NIAID_ChemDB = 
| PDB_ligand = 
| synonyms = AZA

<!-- Chemical and physical data -->
| IUPAC_name = 6-[(1-Methyl-4-nitro-1''H''-imidazol-5-yl)sulfanyl]-7''H''-purine
| C=9 | H=7 | N=7 | O=2 | S=1
| SMILES = Cn1cnc(N(=O)=O)c1Sc2ncnc3nc[nH]c23
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C9H7N7O2S/c1-15-4-14-7(16(17)18)9(15)19-8-5-6(11-2-10-5)12-3-13-8/h2-4H,1H3,(H,10,11,12,13)
| StdInChI_comment = 
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = LMEKQMALGUDUQG-UHFFFAOYSA-N
| density = 
| density_notes = 
| melting_point = 238
| melting_high = 245
| melting_notes = 
| boiling_point = 
| boiling_notes = 
| solubility = 
| sol_units = 
| specific_rotation = 
}}

<!-- Definition and medical uses -->
'''Azathioprine''', sold under the brand name '''Imuran''', among others, is an [[immunosuppressive medication]].<ref name=AHFS2016/> It is used for the treatment of [[rheumatoid arthritis]], [[granulomatosis with polyangiitis]], [[Crohn's disease]], [[ulcerative colitis]], and [[systemic lupus erythematosus]], and in [[kidney transplant]]s to prevent [[transplant rejection|rejection]]. It is listed by the International Agency for Research on Cancer as a [[group 1 carcinogen|group 1 human carcinogen]].<ref name=AHFS2016/><ref>{{cite journal | vauthors = Axelrad JE, Lichtiger S, Yajnik V | title = Inflammatory bowel disease and cancer: The role of inflammation, immunosuppression, and cancer treatment | journal = World Journal of Gastroenterology | volume = 22 | issue = 20 | pages = 4794–4801 | date = May 2016 | pmid = 27239106 | pmc = 4873872 | doi = 10.3748/wjg.v22.i20.4794 | type = Review | doi-access = free }}</ref><ref name=Sing2017>{{cite journal | vauthors = Singer O, McCune WJ | title = Update on maintenance therapy for granulomatosis with polyangiitis and microscopic polyangiitis | journal = Current Opinion in Rheumatology | volume = 29 | issue = 3 | pages = 248–253 | date = May 2017 | pmid = 28306595 | doi = 10.1097/BOR.0000000000000382 | s2cid = 35805200 }}</ref><ref>{{cite journal | vauthors = Jordan N, D'Cruz D | title = Current and emerging treatment options in the management of lupus | journal = ImmunoTargets and Therapy | volume = 5 | pages = 9–20 | date = 2016 | pmid = 27529058 | pmc = 4970629 | doi = 10.2147/ITT.S40675 | doi-access = free }}</ref> It is taken by mouth or [[intravenous|injected into a vein]].<ref name=AHFS2016>{{cite web|title=Azathioprine|url=https://www.drugs.com/monograph/Azathioprine.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20160820215808/https://www.drugs.com/monograph/azathioprine.html|archive-date=20 August 2016}}</ref>

<!-- Side effects and mechanism -->
Common side effects include [[bone marrow suppression|bone-marrow suppression]] and [[vomiting]].<ref name=AHFS2016/> Bone-marrow suppression is especially common in people with a [[genetics|genetic]] deficiency of the enzyme [[thiopurine S-methyltransferase]].<ref name=AHFS2016/> Other serious risk factors include an increased risk of certain [[cancer]]s.<ref name=AHFS2016/> Use during [[pregnancy]] may result in harm to the baby.<ref name=AHFS2016/> Azathioprine belongs to the [[purine analogue]]s subclass of [[antimetabolite]]s family of medications.<ref name=AHFS2016/><ref name=Sam2016/> It works via [[6-thioguanine]] to disrupt the making of [[RNA]] and [[DNA]] by cells.<ref name=AHFS2016/><ref name=Sam2016/>

<!-- History and culture -->
Azathioprine was first made in 1957.<ref name=Sam2016>{{cite book| vauthors = Sami N |title=Autoimmune Bullous Diseases: Approach and Management|date=2016|publisher=Springer|isbn=9783319267289|page=83|url=https://books.google.com/books?id=eMSbCwAAQBAJ&pg=PA83|url-status=live|archive-url=https://web.archive.org/web/20161221162220/https://books.google.ca/books?id=eMSbCwAAQBAJ&pg=PA83|archive-date=2016-12-21}}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref> In 2018, it was the 358th most commonly prescribed medication in the United States, with more than 800,000 prescriptions.<ref>{{cite web | title = Azathioprine - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Azathioprine | access-date = 7 October 2022}}</ref>
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==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 disease]]s, 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.<ref name="derma">{{cite journal | vauthors = Patel AA, Swerlick RA, McCall CO | title = Azathioprine in dermatology: the past, the present, and the future | journal = Journal of the American Academy of Dermatology | volume = 55 | issue = 3 | pages = 369–389 | date = September 2006 | pmid = 16908341 | doi = 10.1016/j.jaad.2005.07.059 }}</ref> 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]].<ref name="pmid12891528">{{cite journal | vauthors = Evans WE | title = Pharmacogenetics of thiopurine S-methyltransferase and thiopurine therapy | journal = Therapeutic Drug Monitoring | volume = 26 | issue = 2 | pages = 186–191 | date = April 2004 | pmid = 15228163 | doi = 10.1097/00007691-200404000-00018 | s2cid = 34015182 }}</ref>

In the United States, it is approved by the [[Food and Drug Administration]] for use in [[kidney transplantation]] from human donors, and for rheumatoid arthritis.<ref name="ahf" >{{cite book | title = AHFS Drug Information 2012 |date=January 2012 | publisher = American Society of Health-System Pharmacists | isbn = 978-1-58528-267-8 | chapter =Azathioprine, Azathioprine Sodium | author =American Society of Health-System Pharmacists | author-link =American Society of Health-System Pharmacists }}</ref>

===Transplantation===
Azathioprine is used to prevent rejections of kidney or liver [[allograft]]s, usually in conjunction with other therapies, including [[corticosteroids]], other immunosuppressants, and local [[radiation therapy]].<ref>{{cite journal | vauthors = Nuyttens JJ, Harper J, Jenrette JM, Turrisi AT | title = Outcome of radiation therapy for renal transplant rejection refractory to chemical immunosuppression | journal = Radiotherapy and Oncology | volume = 74 | issue = 1 | pages = 17–19 | date = January 2005 | pmid = 15683663 | doi = 10.1016/j.radonc.2004.08.011 }}</ref><ref name="myco" /> The administration protocol starts either at the time of transplantation or within the following two days.<ref name="ahf" />

===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.<ref>{{cite journal | vauthors = Suarez-Almazor ME, Spooner C, Belseck E | title = Azathioprine for treating rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | volume = 2010 | issue = 4 | pages = CD001461 | year = 2000 | pmid = 11034720 | pmc = 8406472 | doi = 10.1002/14651858.CD001461 | veditors = Suarez-Almazor ME }}</ref> [[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.<ref name="ahf" />

===Inflammatory bowel disease===
Azathioprine has been used in the management of moderate to severe chronically active Crohn's disease,<ref name="art">{{cite journal | vauthors = Sandborn WJ | title = Azathioprine: state of the art in inflammatory bowel disease | journal = Scandinavian Journal of Gastroenterology. Supplement | volume = 225 | issue = 234 | pages = 92–99 | year = 1998 | pmid = 9515759 | doi = 10.1080/003655298750027290 }}</ref> to maintain [[clinical remission]] (absence of disease activity) in corticosteroid-dependent patients,<ref>{{cite journal | vauthors = Biancone L, Tosti C, Fina D, Fantini M, De Nigris F, Geremia A, Pallone F | title = Review article: maintenance treatment of Crohn's disease | journal = Alimentary Pharmacology & Therapeutics | volume = 17 | issue = Suppl 2 | pages = 31–37 | date = June 2003 | pmid = 12786610 | doi = 10.1046/j.1365-2036.17.s2.20.x | s2cid = 23554085 }}</ref> and to provide benefit in people with [[Fistula|fistulizing]] Crohn's disease.<ref>{{cite journal | vauthors = Rutgeerts P | title = Review article: treatment of perianal fistulizing Crohn's disease | journal = Alimentary Pharmacology & Therapeutics | volume = 20 | issue = Suppl 4 | pages = 106–110 | date = October 2004 | pmid = 15352905 | doi = 10.1111/j.1365-2036.2004.02060.x | s2cid = 71968695 | doi-access = free }}</ref> The onset of action is slow, and several months may be required to achieve a clinical response.<ref name="art" />

Azathioprine treatment is associated with an increased risk of [[lymphoma]], but whether this is due to the drug or a predisposition related to Crohn's disease is unclear.<ref name=Kan2005>{{cite journal | vauthors = Kandiel A, Fraser AG, Korelitz BI, Brensinger C, Lewis JD | title = Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine | journal = Gut | volume = 54 | issue = 8 | pages = 1121–1125 | date = August 2005 | pmid = 16009685 | pmc = 1774897 | doi = 10.1136/gut.2004.049460 }}</ref> Lower doses of azathioprine are used as a therapy in children with refractory or corticosteroid-dependent Crohn's disease, without causing many side effects.<ref>{{cite journal | vauthors = Kirschner BS | title = Safety of azathioprine and 6-mercaptopurine in pediatric patients with inflammatory bowel disease | journal = Gastroenterology | volume = 115 | issue = 4 | pages = 813–821 | date = October 1998 | pmid = 9753482 | doi = 10.1016/S0016-5085(98)70251-3 | doi-access = free }}</ref> It may also be used to prevent flares in those with [[ulcerative colitis]].<ref>{{cite journal | vauthors = Timmer A, Patton PH, Chande N, McDonald JW, MacDonald JK | title = Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis | journal = The Cochrane Database of Systematic Reviews | volume = 2016 | issue = 5 | pages = CD000478 | date = May 2016 | pmid = 27192092 | pmc = 7034525 | doi = 10.1002/14651858.CD000478.pub4 }}</ref>

===Others===
Azathioprine is sometimes used in systemic lupus erythematosus, requiring a maintenance dose of 15&nbsp;mg or higher of [[prednisone]] in those who experience recurrent flares.<ref name=Abu2001>{{cite journal | vauthors = Abu-Shakra M, Shoenfeld Y | title = Azathioprine therapy for patients with systemic lupus erythematosus | journal = Lupus | volume = 10 | issue = 3 | pages = 152–153 | year = 2001 | pmid = 11315344 | doi = 10.1191/096120301676669495 | s2cid = 71558242 }}</ref>

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.<ref name="derma" /><ref>{{cite journal | vauthors = Olszewska M, Kolacinska-Strasz Z, Sulej J, Labecka H, Cwikla J, Natorska U, Blaszczyk M | title = Efficacy and safety of cyclophosphamide, azathioprine, and cyclosporine (ciclosporin) as adjuvant drugs in pemphigus vulgaris | journal = American Journal of Clinical Dermatology | volume = 8 | issue = 2 | pages = 85–92 | year = 2007 | pmid = 17428113 | doi = 10.2165/00128071-200708020-00004 | s2cid = 10699017 }}</ref><ref>{{cite journal | vauthors = Richman DP, Agius MA | title = Treatment of autoimmune myasthenia gravis | journal = Neurology | volume = 61 | issue = 12 | pages = 1652–1661 | date = December 2003 | pmid = 14694025 | doi = 10.1212/01.wnl.0000098887.24618.a0 | s2cid = 24755812 }}</ref> Azathioprine is also used to maintain remission in people who have granulomatosis with polyangiitis.<ref name=Sing2017/>

It can be very effective in eczema and atopic dermatitis, though it is not commonly used.<ref name="derma" /> The British National Eczema Society lists it as a [[Drug of last resort|third-line treatment]] for severe to moderate cases of these skin diseases.<ref>{{cite journal | vauthors = Meggitt SJ, Gray JC, Reynolds NJ | title = Azathioprine dosed by thiopurine methyltransferase activity for moderate-to-severe atopic eczema: a double-blind, randomised controlled trial | journal = Lancet | volume = 367 | issue = 9513 | pages = 839–846 | date = March 2006 | pmid = 16530578 | doi = 10.1016/S0140-6736(06)68340-2 | s2cid = 1616660 }}</ref>

It was widely used to treat multiple sclerosis until the first half of the 1990s. Concerns about increased risk of [[malignancy]] have led to a decreased use, yet it is still used in maintenance treatment for people who frequently [[relapse]].<ref>{{cite journal | vauthors = Casetta I, Iuliano G, Filippini G | title = Azathioprine for multiple sclerosis | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 80 | issue = 2 | pages = 131–2; discussion 132 | date = February 2009 | pmid = 19151017 | doi = 10.1136/jnnp.2008.144972 | s2cid = 207001537 }}</ref> 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 and [[Interferon-beta|interferon beta]], conflicting conclusions regarding cancer, and the potential for long-term risks.<ref>{{cite journal | vauthors = Casetta I, Iuliano G, Filippini G | title = Azathioprine for multiple sclerosis | journal = The Cochrane Database of Systematic Reviews | volume = 2007 | issue = 4 | pages = CD003982 | date = October 2007 | pmid = 17943809 | pmc = 6823213 | doi = 10.1002/14651858.CD003982.pub2 }}</ref>

A widely used therapy for [[idiopathic pulmonary fibrosis]] was azathioprine in combination with prednisone and ''N''-[[acetylcysteine]]. A 2012 study showed that this combination produced worse outcomes than a placebo.<ref>{{cite journal | vauthors = Raghu G, Anstrom KJ, King TE, Lasky JA, Martinez FJ | title = Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis | journal = The New England Journal of Medicine | volume = 366 | issue = 21 | pages = 1968–1977 | date = May 2012 | pmid = 22607134 | pmc = 3422642 | doi = 10.1056/NEJMoa1113354 }}</ref>

==Adverse effects==
[[File:000040lg Azathioprine 50 MG Oral Tablet.jpg|thumb|260px|Two generic azathioprine oral tablets, 50 mg each]]
Nausea and vomiting are common adverse effects, especially at the beginning of 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 (medical)|fatigue]], and [[rashes]]. Hair loss is often seen in transplant patients receiving the drug but rarely occurs under other indications. Because azathioprine [[bone marrow suppression|suppresses the bone marrow]], patients can develop [[anaemia]] and be more susceptible to [[infection]]; regular monitoring of the [[blood count]] is recommended during treatment.<ref name="ahf" /><ref name="Austria-Codex">{{cite book|title=Austria-Codex|editor=Jasek, W|publisher=Österreichischer Apothekerverlag|location=Vienna|year=2007|edition=62nd|pages=4103–9|isbn=978-3-85200-181-4|language=de}}</ref> [[Acute pancreatitis]] can also occur, especially in patients with Crohn's disease.<ref name="APT2004">{{cite journal | vauthors = Weersma RK, Peters FT, Oostenbrug LE, van den Berg AP, van Haastert M, Ploeg RJ, Posthumus MD, Homan van der Heide JJ, Jansen PL, van Dullemen HM | title = Increased incidence of azathioprine-induced pancreatitis in Crohn's disease compared with other diseases | journal = Alimentary Pharmacology & Therapeutics | volume = 20 | issue = 8 | pages = 843–850 | date = October 2004 | pmid = 15479355 | doi = 10.1111/j.1365-2036.2004.02197.x | s2cid = 21873238 }}</ref> 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.<ref>{{cite journal | vauthors = Pecher D, Zelinkova Z, Lucenicova J, Peppelenbosch M, Dokupilova S, Mikusova V, Mikus P | title = Porous graphitic carbon based chromatography hyphenated with mass spectrometry: A new strategy for profiling thiopurine nucleotides in patients with inflammatory bowel diseases | journal = Analytica Chimica Acta | volume = 1137 | issue = 1137 | pages = 64–73 | date = November 2020 | pmid = 33153610 | doi = 10.1016/j.aca.2020.08.064 | bibcode = 2020AcAC.1137...64P | s2cid = 225287631 }}</ref>

It is listed by the [[International Agency for Research on Cancer]] as a [[List of IARC Group 1 carcinogens|group 1 carcinogen]] (carcinogenic to humans).<ref name="IARC-1987" />

===Pharmacogenetics===

The enzyme [[thiopurine S-methyltransferase]] (TPMT) is responsible for various activation and deactivation steps in azathioprine's mechanism of action.<ref>{{cite book | title=Medical Genetics Summaries | chapter=Azathioprine Therapy and TPMT Genotype | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK100661/ | veditors=Pratt VM, McLeod HL, Rubinstein WS, Scott SA, Dean LC, Kattman BL, Malheiro AJ | display-editors=3 | publisher=[[National Center for Biotechnology Information]] (NCBI) | year=2012 | pmid=28520349 | id=Bookshelf ID: NBK100661 | vauthors=Dean L | url=https://www.ncbi.nlm.nih.gov/books/NBK61999/ }}</ref> The first metabolic step that azathioprine undergoes in the body is the conversion to [[mercaptopurine|6-mercaptopurine]] (6-MP; see [[#Pharmacokinetics|Pharmacokinetics]]), which is itself an [[Immunosuppressive drug|immunosuppressant]] [[prodrug]].<ref name="pmid19952870">{{cite journal | vauthors = Zaza G, Cheok M, Krynetskaia N, Thorn C, Stocco G, Hebert JM, McLeod H, Weinshilboum RM, Relling MV, Evans WE, Klein TE, Altman RB | title = Thiopurine pathway | journal = Pharmacogenetics and Genomics | volume = 20 | issue = 9 | pages = 573–574 | date = September 2010 | pmid = 19952870 | pmc = 3098750 | doi = 10.1097/FPC.0b013e328334338f }}</ref><ref name="pmid24707136">{{cite journal | vauthors = Stocco G, Pelin M, Franca R, De Iudicibus S, Cuzzoni E, Favretto D, Martelossi S, Ventura A, Decorti G | title = Pharmacogenetics of azathioprine in inflammatory bowel disease: a role for glutathione-S-transferase? | journal = World Journal of Gastroenterology | volume = 20 | issue = 13 | pages = 3534–3541 | date = April 2014 | pmid = 24707136 | pmc = 3974520 | doi = 10.3748/wjg.v20.i13.3534 | doi-access = free }}</ref> 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.<ref name="pmid19952870"/><ref name="pmid17691917">{{cite journal | vauthors = Fujita K, Sasaki Y | title = Pharmacogenomics in drug-metabolizing enzymes catalyzing anticancer drugs for personalized cancer chemotherapy | journal = Current Drug Metabolism | volume = 8 | issue = 6 | pages = 554–562 | date = August 2007 | pmid = 17691917 | doi = 10.2174/138920007781368890 | url = http://www.bentham-direct.org/pages/content.php?CDM/2007/00000008/00000006/0002F.SGM | url-status = usurped | archive-url = https://archive.today/20130112103320/http://www.bentham-direct.org/pages/content.php?CDM/2007/00000008/00000006/0002F.SGM | archive-date = 2013-01-12 | url-access = subscription }}</ref> Certain [[genetic variation]]s 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 variation]]s may have increased levels of TGN metabolites and an increased risk of severe bone-marrow suppression ([[myelosuppression]]) when receiving azathioprine.<ref name="pmid21270794">{{cite journal | vauthors = Relling MV, Gardner EE, Sandborn WJ, Schmiegelow K, Pui CH, Yee SW, Stein CM, Carrillo M, Evans WE, Klein TE | title = Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing | journal = Clinical Pharmacology and Therapeutics | volume = 89 | issue = 3 | pages = 387–391 | date = March 2011 | pmid = 21270794 | pmc = 3098761 | doi = 10.1038/clpt.2010.320 | others = Clinical Pharmacogenetics Implementation Consortium }}</ref> 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.<ref name="pmid21270794"/><ref name="Mutschler">{{cite book| vauthors = Mutschler E, Schäfer-Korting M | title=Arzneimittelwirkungen|pages = 107, 936|language=de|location=Stuttgart|publisher=Wissenschaftliche Verlagsgesellschaft|year=2001|edition=8th|isbn=978-3-8047-1763-3}}</ref> However, an assay of TPMT activity in [[red blood cell]]s or a ''TPMT'' [[genetic test]] can identify patients with reduced TPMT enzyme activity, allowing for the adjustment of azathioprine dose or avoidance of the drug entirely.<ref name="pmid21270794"/><ref>{{cite journal | vauthors = Payne K, Newman W, Fargher E, Tricker K, Bruce IN, Ollier WE | title = TPMT testing in rheumatology: any better than routine monitoring? | journal = Rheumatology | volume = 46 | issue = 5 | pages = 727–729 | date = May 2007 | pmid = 17255139 | doi = 10.1093/rheumatology/kel427 | doi-access = free }}</ref> The FDA-approved drug label for azathioprine recommends testing for TPMT activity to identify patients at risk for [[myelotoxicity]].<ref>{{cite web|url=http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aaa6c540-4c84-48a0-939c-cd423134fa2a|title=Label: Imuran - azathioprine tablet|access-date=19 October 2014|url-status=live|archive-url=https://web.archive.org/web/20141020220249/http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aaa6c540-4c84-48a0-939c-cd423134fa2a|archive-date=20 October 2014}}</ref> Indeed, testing for TPMT activity is one of the few examples of [[pharmacogenetics]] being translated into routine clinical care.<ref name="pmid20154640">{{cite journal | vauthors = Wang L, Pelleymounter L, Weinshilboum R, Johnson JA, Hebert JM, Altman RB, Klein TE | title = Very important pharmacogene summary: thiopurine S-methyltransferase | journal = Pharmacogenetics and Genomics | volume = 20 | issue = 6 | pages = 401–405 | date = June 2010 | pmid = 20154640 | pmc = 3086840 | doi = 10.1097/FPC.0b013e3283352860 }}</ref> Missense SNP in [[NUDT15]] (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.<ref>{{cite journal | vauthors = Yang SK, Hong M, Baek J, Choi H, Zhao W, Jung Y, Haritunians T, Ye BD, Kim KJ, Park SH, Park SK, Yang DH, Dubinsky M, Lee I, McGovern DP, Liu J, Song K | title = A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia | journal = Nature Genetics | volume = 46 | issue = 9 | pages = 1017–1020 | date = September 2014 | pmid = 25108385 | pmc = 4999337 | doi = 10.1038/ng.3060 }}</ref>

===Cancers===
Azathioprine is listed as a human carcinogen in the 12th Report on Carcinogens by the [[National Toxicology Program]] of [[United States Department of Health and Human Services|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."<ref name="roc2011">{{cite web|author=National Toxicology Program|author-link=National Toxicology Program|title=Report On Carcinogens – Twelfth Edition – 2011|date=10 June 2011|url=https://ntp.niehs.nih.gov/go/roc12|publisher=[[National Toxicology Program]]|access-date=June 20, 2012|url-status=live|archive-url=https://web.archive.org/web/20120716214414/http://ntp.niehs.nih.gov/ntp/roc/twelfth/roc12.pdf|archive-date=16 July 2012}}</ref> Since August 2009, the U.S. FDA has required warnings to be placed on packaging with respect to increased risks of certain cancers.<ref>{{cite web |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm175803.htm |title=FDA: Cancer Warnings Required for TNF Blockers |date=August 4, 2009 |publisher=FDA |access-date=June 20, 2012 |url-status=dead |archive-url=https://web.archive.org/web/20120703083928/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm175803.htm |archive-date=July 3, 2012 }}</ref>

The risks involved seem to be related both to the duration and the dosage used. People who have previously been treated with an [[alkylating antineoplastic agent|alkylating agent]] may have an excessive risk of cancers if treated with azathioprine. Epidemiological studies by [[International Agency for Research on Cancer]] have provided "sufficient" evidence of azathioprine carcinogenicity in humans ([[List of IARC Group 1 carcinogens|group 1]]),<ref name="IARC-1981">{{cite journal| author = International Agency for Research on Cancer (IARC)| author-link = International Agency for Research on Cancer| year = 1981| url = http://www.inchem.org/documents/iarc/vol26/azathioprine.html| title = Azathioprine – 5. Summary of Data Reported and Evaluation| journal = Summaries & Evaluations| volume = 26| page = 47| url-status = live| archive-url = https://web.archive.org/web/20060906064533/http://www.inchem.org/documents/iarc/vol26/azathioprine.html| archive-date = 2006-09-06}}</ref> although the methodology of past studies and the possible underlying mechanisms are questioned.<ref name="MutatRes1993-Gombar">{{cite journal | vauthors = Gombar VK, Enslein K, Blake BW | title = Carcinogenicity of azathioprine: an S-AR investigation | journal = Mutation Research | volume = 302 | issue = 1 | pages = 7–12 | date = May 1993 | pmid = 7683109 | doi = 10.1016/0165-7992(93)90083-8 }}</ref>

The various diseases requiring transplantation may in themselves increase the risks of [[non-Hodgkin lymphoma]], [[squamous cell carcinoma]]s of the skin, [[Cholangiocarcinoma|hepatobiliary carcinomas]], and [[Mesenchyme|mesenchymal tumours]] to which azathioprine may add additional risks. Those receiving azathioprine for rheumatoid arthritis may have a lower risk than those undergoing transplantation.<ref name="IARC-1987">{{cite journal| author = International Agency for Research on Cancer (IARC)| author-link = International Agency for Research on Cancer| year = 1987| url = http://www.inchem.org/documents/iarc/suppl7/azathioprine.html| title = Azathioprine| journal = Summaries & Evaluations| issue = suppl. 7| page = 119| url-status = live| archive-url = https://web.archive.org/web/20060604004241/http://www.inchem.org/documents/iarc/suppl7/azathioprine.html| archive-date = 2006-06-04}}</ref>

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.<ref name="gut">{{cite journal | vauthors = McGovern DP, Jewell DP | title = Risks and benefits of azathioprine therapy | journal = Gut | volume = 54 | issue = 8 | pages = 1055–1059 | date = August 2005 | pmid = 16009676 | pmc = 1774869 | doi = 10.1136/gut.2004.053231 }}</ref> 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.<ref>{{cite web |url=https://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm258794.htm |title=Imuran (azathioprine) Tablets and Injection |date=May 2011 |publisher=FDA |access-date=June 20, 2012 |url-status=dead |archive-url=https://web.archive.org/web/20120302092152/https://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm258794.htm |archive-date=March 2, 2012 }}</ref>

====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.<ref name="bbcsb">{{cite web |url=http://news.bbc.co.uk/2/hi/health/4248356.stm |title=Skin cancer alert for organ drug |date=September 15, 2005 |website=[[BBC Online]] |publisher=[[BBC News]] |access-date=June 10, 2012 |url-status=live |archive-url=https://web.archive.org/web/20121014205054/http://news.bbc.co.uk/2/hi/health/4248356.stm |archive-date=October 14, 2012 }}</ref> 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.<ref>{{cite journal | vauthors = O'Donovan P, Perrett CM, Zhang X, Montaner B, Xu YZ, Harwood CA, McGregor JM, Walker SL, Hanaoka F, Karran P | title = Azathioprine and UVA light generate mutagenic oxidative DNA damage | journal = Science | volume = 309 | issue = 5742 | pages = 1871–1874 | date = September 2005 | pmid = 16166520 | pmc = 2426755 | doi = 10.1126/science.1114233 | bibcode = 2005Sci...309.1871O }}</ref>

==Overdose==
Large, single doses are generally well tolerated; a patient who took 7.5&nbsp;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 ulcer]]s, and spontaneous bleeding, all of which are consequences of its bone-marrow suppression.<ref name="Austria-Codex" />

== Interactions ==

Other purine analogues, such as [[allopurinol]], inhibit [[xanthine oxidase]], the enzyme that breaks down azathioprine, thus increasing the toxicity of azathioprine.<ref name="pmid18506437">{{cite journal | vauthors = Sahasranaman S, Howard D, Roy S | title = Clinical pharmacology and pharmacogenetics of thiopurines | journal = European Journal of Clinical Pharmacology | volume = 64 | issue = 8 | pages = 753–767 | date = August 2008 | pmid = 18506437 | doi = 10.1007/s00228-008-0478-6 | s2cid = 27475772 }}</ref> Low doses of allopurinol, though, have been shown to safely enhance the efficacy of azathioprine, especially in inflammatory bowel disease nonresponders.<ref>{{cite journal | vauthors = Chocair P, Duley J, Simmonds HA, Cameron JS, Ianhez L, Arap S, Sabbaga E | title = Low-dose allopurinol plus azathioprine/cyclosporin/prednisolone, a novel immunosuppressive regimen | journal = Lancet | volume = 342 | issue = 8863 | pages = 83–84 | date = July 1993 | pmid = 8100914 | doi = 10.1016/0140-6736(93)91287-V | s2cid = 13419507 }}</ref><ref>{{cite journal | vauthors = Sparrow MP, Hande SA, Friedman S, Lim WC, Reddy SI, Cao D, Hanauer SB | title = Allopurinol safely and effectively optimizes tioguanine metabolites in inflammatory bowel disease patients not responding to azathioprine and mercaptopurine | journal = Alimentary Pharmacology & Therapeutics | volume = 22 | issue = 5 | pages = 441–446 | date = September 2005 | pmid = 16128682 | doi = 10.1111/j.1365-2036.2005.02583.x | s2cid = 9356163 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Sparrow MP, Hande SA, Friedman S, Cao D, Hanauer SB | title = Effect of allopurinol on clinical outcomes in inflammatory bowel disease nonresponders to azathioprine or 6-mercaptopurine | journal = Clinical Gastroenterology and Hepatology | volume = 5 | issue = 2 | pages = 209–214 | date = February 2007 | pmid = 17296529 | doi = 10.1016/j.cgh.2006.11.020 | doi-access = free }}</ref> This may still lead to lower lymphocyte counts and higher rates of infection, so the combination requires careful monitoring.<ref>{{cite journal | vauthors = Govani SM, Higgins PD | title = Combination of thiopurines and allopurinol: adverse events and clinical benefit in IBD | journal = Journal of Crohn's & Colitis | volume = 4 | issue = 4 | pages = 444–449 | date = October 2010 | pmid = 21122542 | pmc = 3157326 | doi = 10.1016/j.crohns.2010.02.009 }}</ref><ref name="pmid20015102">{{cite journal | vauthors = Ansari A, Patel N, Sanderson J, O'Donohue J, Duley JA, Florin TH | title = Low-dose azathioprine or mercaptopurine in combination with allopurinol can bypass many adverse drug reactions in patients with inflammatory bowel disease | journal = Alimentary Pharmacology & Therapeutics | volume = 31 | issue = 6 | pages = 640–647 | date = March 2010 | pmid = 20015102 | doi = 10.1111/j.1365-2036.2009.04221.x | s2cid = 6000856 | doi-access = free }}</ref>

Azathioprine decreases the effects of the [[anticoagulant]] [[warfarin]] and of [[Non-depolarizing blocking agent|nondepolarizing]] muscle relaxants, but increases the effect of [[Depolarizing blocking agent|depolarizing]] muscle relaxants.<ref name="Austria-Codex" /> It can also interfere with [[Niacin (nutrient)|niacin]] (vitamin B<sub>3</sub>), resulting in at least one case to [[pellagra]] and fatal medullary aplasia.<ref>{{cite journal | vauthors = Oliveira A, Sanches M, Selores M | title = Azathioprine-induced pellagra | journal = The Journal of Dermatology | volume = 38 | issue = 10 | pages = 1035–1037 | date = October 2011 | pmid = 21658113 | doi = 10.1111/j.1346-8138.2010.01189.x | s2cid = 3396280 }}</ref>

==Pregnancy and breastfeeding==
Azathioprine can cause birth defects.<ref name="BNF">{{cite book | title = British National Formulary, Issue 45 |date=March 2003 | publisher = [[British Medical Association]] | location = [[London]] | isbn = 978-0-85369-555-4 | vauthors = Mehta DK | collaboration =[[Pharmaceutical Society of Great Britain]] |title-link=British National Formulary }}</ref><ref>{{cite journal | vauthors = Cleary BJ, Källén B | title = Early pregnancy azathioprine use and pregnancy outcomes | journal = Birth Defects Research. Part A, Clinical and Molecular Teratology | volume = 85 | issue = 7 | pages = 647–654 | date = July 2009 | pmid = 19343728 | doi = 10.1002/bdra.20583 }}</ref><ref>{{cite journal | vauthors = Tagatz GE, Simmons RL | title = Pregnancy after renal transplantation | journal = Annals of Internal Medicine | volume = 82 | issue = 1 | pages = 113–114 | date = January 1975 | pmid = 799904 | doi = 10.7326/0003-4819-82-1-113 }}</ref> 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]].<ref name=mercaptopurine_birth_outcome>{{cite journal | vauthors = Nørgård B, Pedersen L, Fonager K, Rasmussen SN, Sørensen HT | title = Azathioprine, mercaptopurine and birth outcome: a population-based cohort study | journal = Alimentary Pharmacology & Therapeutics | volume = 17 | issue = 6 | pages = 827–834 | date = March 2003 | pmid = 12641505 | doi = 10.1046/j.1365-2036.2003.01537.x | s2cid = 25314258 | doi-access = free }}</ref> Birth defects in a child whose father was taking azathioprine have also been reported.<ref>{{cite journal | vauthors = Tallent MB, Simmons RL, Najarian JS | title = Birth defects in child of male recipient of kidney transplant | journal = JAMA | volume = 211 | issue = 11 | pages = 1854–1855 | date = March 1970 | pmid = 4905893 | doi = 10.1001/jama.211.11.1854 }}</ref> Although no adequate and [[controlled study|well-controlled studies]] have taken place in humans, when given to [[animal]]s in doses equivalent to human dosages, teratogenesis was observed.<ref>{{cite journal | vauthors = Polifka JE, Friedman JM | title = Teratogen update: azathioprine and 6-mercaptopurine | journal = Teratology | volume = 65 | issue = 5 | pages = 240–261 | date = May 2002 | pmid = 11967923 | doi = 10.1002/tera.10043 | citeseerx = 10.1.1.566.7676 }}</ref> 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.<ref name="BNF"/>

Traditionally, as for all [[cytotoxic drug]]s, the manufacturer advises not to breastfeed whilst taking azathioprine, but the "lactation risk category" reported by Thomas Hale in his book ''Medications and Mothers' Milk'' lists azathioprine as "L3", termed "moderately safe".<ref>{{cite book | title = Medications and Mothers' Milk: A Manual of Lactational Pharmacology |date=April 2010 | publisher = Hale Pub. | isbn = 978-0-9823379-9-8 | vauthors = Hale TW }}</ref>

==Pharmacology==

===Pharmacokinetics===
[[File:AZA metabolism.svg|class=skin-invert-image|thumb|520px|[[Metabolic pathway]] for azathioprine (AZA).<ref>{{cite journal | vauthors = Cronstein BN | title = Pharmacogenetics in the rheumatic diseases | journal = Annals of the Rheumatic Diseases | volume = 63 | issue = Suppl 2 | pages = ii25–ii27 | date = November 2004 | pmid = 15479867 | pmc = 1766779 | doi = 10.1136/ard.2004.028217 }}</ref><ref name="Karran">{{cite journal | vauthors = Karran P, Attard N | title = Thiopurines in current medical practice: molecular mechanisms and contributions to therapy-related cancer | journal = Nature Reviews. Cancer | volume = 8 | issue = 1 | pages = 24–36 | date = January 2008 | pmid = 18097462 | doi = 10.1038/nrc2292 | s2cid = 23327335 }}</ref> [[Active metabolite]]s are highlighted.
{{hlist
| 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: thio[[guanosine 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 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 to [[plasma proteins]] while circulating in the bloodstream.<ref name="derma" /><ref name="Austria-Codex" /><ref name="Arzneistoff-Profile">{{cite book|title=Arzneistoff-Profile|editor1=Dinnendahl, V |editor2=Fricke, U |publisher=Govi Pharmazeutischer Verlag|location=Eschborn, Germany|year=2011|edition=25th|volume=2|isbn=978-3-7741-9846-3|language=de}}</ref><ref name="Steinhilber">{{cite book|title=Medizinische Chemie| vauthors = Steinhilber D, Schubert-Zsilavecz M, Roth HJ |publisher=Deutscher Apotheker Verlag|location=Stuttgart|year=2005|page=340|isbn=978-3-7692-3483-1|language=de}}</ref>

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 [[redox|reductive]] cleavage of the [[thioether]] (–[[sulfur|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 thio[[guanosine 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 [[methyl]]ated. The end products of azathioprine metabolism are [[thiouric acid]] (38%) and various methylated and [[hydroxyl]]ated purines, which are excreted via the urine.<ref name="Mutschler" /><ref name="Arzneistoff-Profile" /><ref name="Steinhilber" />

===Mechanism of action===
Azathioprine inhibits [[Purine metabolism#Biosynthesis|purine synthesis]]. Purines are needed to produce DNA and RNA. By inhibiting purine synthesis, less DNA and RNA are produced for the synthesis of [[white blood cell]]s, thus causing immunosuppression.

{{Technical|section|date=December 2014}}
Azathioprine is converted within tissues to 6-MP, some of which is converted, in turn, to [[6-thioguanine]] by the addition of an amino group. Both 6-MP and 6-thioguanine are conjugated with [[ribose]] and then phosphorylated to form the [[nucleotides]] [[thioinosinic acid]] and thioguanylic acid, respectively.<ref name="pmid12891528" /> These nucleotides masquerade, respectively, as [[inosinic acid]] and [[guanylic 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, halting [[DNA replication|replication]].
* The nucleotides act to inhibit glutamine-[[phosphoribosyl pyrophosphate amidotransferase]] (GPAT), one of the enzymes involved in [[purine biosynthesis]], one of the earlier steps in the synthesis of DNA and RNA. They achieve GPAT inhibition through a form of negative feedback called [[product inhibition]].<ref name="smpdb">{{cite web|url=http://pathman.smpdb.ca/pathways/SMP00427/pathway |title=Azathioprine Pathway |publisher=Small Molecule Pathway Database |access-date=31 August 2012 |url-status=dead |archive-url=https://web.archive.org/web/20120702065409/http://pathman.smpdb.ca/pathways/SMP00427/pathway |archive-date=2 July 2012 }}</ref> Because actively replicating cells (such as cancer cells and the [[T cell]]s and [[B cell]]s of the [[immune system]]) are most active in synthesizing purine, making new DNA, these cells are most strongly affected.<ref name=Example2006>{{cite journal | vauthors = Maltzman JS, Koretzky GA | title = Azathioprine: old drug, new actions | journal = The Journal of Clinical Investigation | volume = 111 | issue = 8 | pages = 1122–1124 | date = April 2003 | pmid = 12697731 | pmc = 152947 | doi = 10.1172/JCI18384 }}</ref><ref name="derma" />
* A portion of the nucleotides is additionally phosphorylated to the triphosphate forms. These bind to [[Guanosine triphosphate|GTP]]-binding protein [[Rac1]], blocking synthesis of the protein [[Bcl-xL]], thus sending activated T&nbsp;cells and [[mononuclear cell]]s into [[apoptosis]] (programmed cell death). Increased apoptosis of mononuclear cells is seen in inflammatory bowel disease patients treated with azathioprine.<ref name=Example2006 />

==Chemistry==
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&nbsp;°C. It is practically insoluble in water and only slightly soluble in [[lipophilic]] solvents such as chloroform, ethanol, and diethyl ether. It dissolves in alkaline aqueous solutions, where it [[hydrolyze]]s to 6-MP.<ref name="Arzneistoff-Profile" />

Azathioprine is synthesized from 5-chloro-1-methyl-4-nitro-1''H''-imidazole and 6-mercaptopurine in [[dimethyl sulfoxide]].<ref>{{cite patent |country=US |number=3056785 |status=Patent |title = Purine Derivatives |gdate=1962-10-06 |fdate=1960-05-21 | invent1=G. H. Hitchings | invent2=Yonkers | invent3=G. B. Elion }}.</ref> The synthesis of the former starts with an [[amide]] from [[methylamine]] and diethyl [[oxalic acid|oxalate]], which is then cyclized and chlorinated with [[phosphorus pentachloride]];<ref>{{cite journal | vauthors = Blicke FF, Godt HC | title = Diuretics. I. 3-Substituted Paraxanthines | journal = Journal of the American Chemical Society | volume = 76 | issue = 14 | pages = 3653–3655 | year = 1954 | doi = 10.1021/ja01643a015 | bibcode = 1954JAChS..76.3653B }}</ref> the [[nitro group]] is introduced with [[nitric acid|nitric]] and [[sulfuric acid]].

[[File:Azathioprine synthesis.svg|class=skin-invert-image|770px|The whole process of azathioprine synthesis]]

==History==
Azathioprine was synthesized by [[George Herbert Hitchings]] and [[Gertrude Elion]] in 1957 (named BW&nbsp;57-322) to produce 6-MP in a metabolically active, but masked form, and at first used as a [[chemotherapy]] drug.<ref name="nobel" /><ref>{{cite journal | vauthors = Elion GB, Callahan SW, Hitchings GH, Rundles RW | title = The metabolism of 2-amino-6-[(1-methyl-4-nitro-5-imidazolyl)thio]purine (B.W. 57-323) in man | journal = Cancer Chemotherapy Reports | volume = 8 | pages = 47–52 | date = July 1960 | pmid = 13849699 }}</ref><ref>{{cite journal | vauthors = Thiersch JB | title = Effect of 6-(1'-methyl-4'-nitro-5'-imidazolyl)-mercaptopurine and 2-amino-6-(1'-methyl-4'-nitro-5'-imidazolyl)-mercaptopurine on the rat litter in utero | journal = Journal of Reproduction and Fertility | volume = 4 | issue = 3 | pages = 297–302 | date = December 1962 | pmid = 13980986 | doi = 10.1530/jrf.0.0040297 }}</ref>

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 [[antigen]]s.<ref>{{cite journal | vauthors = Schwartz R, Stack J, Dameshek W | title = Effect of 6-mercaptopurine on antibody production | journal = Proceedings of the Society for Experimental Biology and Medicine | volume = 99 | issue = 1 | pages = 164–167 | date = October 1958 | pmid = 13601801 | doi = 10.3181/00379727-99-24281 | s2cid = 8043359 }}</ref> Following the work done by Sir [[Peter Medawar]] and Gertrude Elion in discovering the immunological basis of [[Transplant rejection|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 transplantation|kidney]] and [[heart transplant]]s.<ref>{{cite journal | vauthors = Calne RY | title = The rejection of renal homografts. Inhibition in dogs by 6-mercaptopurine | journal = Lancet | volume = 1 | issue = 7121 | pages = 417–418 | date = February 1960 | pmid = 13807024 | doi = 10.1016/S0140-6736(60)90343-3 }}</ref> 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.<ref name="nobel">{{cite journal | vauthors = Elion GB | title = The purine path to chemotherapy | journal = Science | volume = 244 | issue = 4900 | pages = 41–47 | date = April 1989 | pmid = 2649979 | doi = 10.1126/science.2649979 | bibcode = 1989Sci...244...41E }}</ref><ref name="derma" />

In April 1962, with regimens consisting of azathioprine and prednisone, the transplantation of kidneys to unrelated recipients (allotransplantation) was successful for the first time.<ref name="derma" /><ref>{{cite journal | vauthors = Murray JE, Merrill JP, Harrison JH, Wilson RE, Dammin GJ | title = Prolonged survival of human-kidney homografts by immunosuppressive drug therapy | journal = The New England Journal of Medicine | volume = 268 | issue = 24 | pages = 1315–1323 | date = June 1963 | pmid = 13936775 | doi = 10.1056/NEJM196306132682401 }}</ref> For many years, this kind of dual therapy with azathioprine and [[glucocorticoid]]s 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.<ref>{{cite journal | vauthors = Bakker RC, Hollander AA, Mallat MJ, Bruijn JA, Paul LC, de Fijter JW | title = Conversion from cyclosporine to azathioprine at three months reduces the incidence of chronic allograft nephropathy | journal = Kidney International | volume = 64 | issue = 3 | pages = 1027–1034 | date = September 2003 | pmid = 12911553 | doi = 10.1046/j.1523-1755.2003.00175.x | doi-access = free }}</ref><ref>{{cite journal | vauthors = Henry ML, Sommer BG, Ferguson RM | title = Beneficial effects of cyclosporine compared with azathioprine in cadaveric renal transplantation | journal = American Journal of Surgery | volume = 150 | issue = 5 | pages = 533–536 | date = November 1985 | pmid = 2998215 | doi = 10.1016/0002-9610(85)90431-3 }}</ref><ref>{{cite journal | vauthors = Modry DL, Oyer PE, Jamieson SW, Stinson EB, Baldwin JC, Reitz BA, Dawkins KD, McGregor CG, Hunt SA, Moran M | title = Cyclosporine in heart and heart-lung transplantation | journal = Canadian Journal of Surgery. Journal Canadien de Chirurgie | volume = 28 | issue = 3 | pages = 274–80, 282 | date = May 1985 | pmid = 3922606 }}</ref> 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 infection]]s, and a lower incidence of acute rejection.<ref name="myco">{{cite journal | vauthors = Remuzzi G, Lesti M, Gotti E, Ganeva M, Dimitrov BD, Ene-Iordache B, Gherardi G, Donati D, Salvadori M, Sandrini S, Valente U, Segoloni G, Mourad G, Federico S, Rigotti P, Sparacino V, Bosmans JL, Perico N, Ruggenenti P | title = Mycophenolate mofetil versus azathioprine for prevention of acute rejection in renal transplantation (MYSS): a randomised trial | journal = Lancet | volume = 364 | issue = 9433 | pages = 503–512 | date = August 2004 | pmid = 15302193 | doi = 10.1016/S0140-6736(04)16808-6 | s2cid = 22033113 }}</ref><ref name="HealthTechnolAssess2005-Woodroffe">{{cite journal | vauthors = Woodroffe R, Yao GL, Meads C, Bayliss S, Ready A, Raftery J, Taylor RS | title = Clinical and cost-effectiveness of newer immunosuppressive regimens in renal transplantation: a systematic review and modelling study | journal = Health Technology Assessment | volume = 9 | issue = 21 | pages = 1–194 | date = May 2005 | pmid = 15899149 | doi = 10.3310/hta9210 | doi-access = free }}</ref>

== References ==
{{Reflist}}

== Further reading ==
* {{cite book | title=Medical Genetics Summaries | chapter=Azathioprine Therapy and TPMT Genotype | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK100661/ | veditors=Pratt VM, McLeod HL, Rubinstein WS, Scott SA, Dean LC, Kattman BL, Malheiro AJ | display-editors=3 | publisher=[[National Center for Biotechnology Information]] (NCBI) | year=2012 | pmid=28520349 | id=Bookshelf ID: NBK100661 | vauthors=Dean L | url=https://www.ncbi.nlm.nih.gov/books/NBK61999/ }}

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