Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Allopurinol: Difference between pages

{{Distinguish|haloperidol}}

{{Short description|Medication}}

{{Use dmy dates|date=January 2024}}

{{cs1 config|name-list-style=vanc|display-authors=6}}

{{Infobox drug

| Watchedfields = changed

| verifiedrevid = 477318043

| image = Allopurinol V.1.svg

| width = 150

| alt =

| image2 = Allopurinol_3d_structure.png

| alt2 =

| tradename = Zyloprim, Caplenal, Zyloric, others

| Drugs.com = {{drugs.com|monograph|allopurinol}}

| MedlinePlus = a682673

| DailyMedID = Allopurinol

| pregnancy_AU = B2

| pregnancy_AU_comment = <ref name="Drugs.com Pregnancy" />

| pregnancy_category =

| routes_of_administration = [[Oral administration|Oral]], [[intravenous]]

| ATC_prefix = M04

| ATC_suffix = AA01

| ATC_supplemental =

| legal_AU = S4

| legal_AU_comment = <ref>{{cite web | title=Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/resources/publication/publications/prescription-medicines-registration-new-generic-medicines-and-biosimilar-medicines-2017 | access-date=30 March 2024 | archive-date=6 July 2023 | archive-url=https://web.archive.org/web/20230706023149/https://www.tga.gov.au/resources/publication/publications/prescription-medicines-registration-new-generic-medicines-and-biosimilar-medicines-2017 | url-status=live }}</ref>

| legal_UK = POM

| legal_US = Rx-only

| legal_US_comment = <ref name="Allopurinol FDA label">{{cite web | title=Allopurinol tablet | website=DailyMed | date=13 December 2023 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=30ad5ba2-1cef-4933-b104-0597f6a2aaa2 | access-date=16 January 2024 | archive-date=29 February 2024 | archive-url=https://web.archive.org/web/20240229080042/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=30ad5ba2-1cef-4933-b104-0597f6a2aaa2 | url-status=live }}</ref><ref name=Labelinject />

| bioavailability = 78±20%

| protein_bound = Negligible

| metabolism = [[Liver]] (80% [[oxipurinol]], 10% allopurinol ribosides)

| elimination_half-life = 2 h (oxipurinol 18–30 h)

| IUPHAR_ligand = 6795

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 315-30-0

| PubChem = 135401907

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB00437

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 2010

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 63CZ7GJN5I

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D00224

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEBI = 40279

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 1467

| IUPAC_name = 1''H''-Pyrazolo[3,4-''d'']pyrimidin-4(2''H'')-one

| C = 5

| H = 4

| N = 4

| O = 1

| smiles = C1=NNC2=C1C(=O)NC=N2

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C5H4N4O/c10-5-3-1-8-9-4(3)6-2-7-5/h1-2H,(H2,6,7,8,9,10)

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = OFCNXPDARWKPPY-UHFFFAOYSA-N

<!-- Definition and medical uses -->

'''Allopurinol''' is a [[medication]] used to decrease [[hyperuricemia|high blood uric acid levels]].<ref name=Patcher2006rev>{{cite journal | vauthors = Pacher P, Nivorozhkin A, Szabó C | title = Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol | journal = Pharmacological Reviews | volume = 58 | issue = 1 | pages = 87–114 | date = March 2006 | pmid = 16507884 | pmc = 2233605 | doi = 10.1124/pr.58.1.6 }}</ref> It is specifically used to prevent [[gout]], prevent specific types of [[kidney stones]] and for the high uric acid levels that can occur with [[chemotherapy]].<ref name=WHO2008>{{cite book | title = WHO Model Formulary 2008 | year = 2009 | isbn = 9789241547659 | vauthors = ((World Health Organization)) | veditors = Stuart MC, Kouimtzi M, Hill SR | hdl = 10665/44053 | author-link = World Health Organization | publisher = World Health Organization | hdl-access=free | page = 39}}</ref><ref name=AHFS2016/> It is taken [[Oral administration|orally]] (by mouth) or [[intravenously]] (injected into a vein).<ref name=AHFS2016>{{cite web|title=Allopurinol|url=https://www.drugs.com/monograph/allopurinol.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20160429134301/http://www.drugs.com/monograph/allopurinol.html|archive-date=29 April 2016}}</ref>

<!-- Side effects and mechanism -->

Common side effects when used orally include itchiness and rash.<ref name=AHFS2016/> Common side effects when used by injection include [[vomiting]] and [[kidney problems]].<ref name=AHFS2016/> While not recommended historically, starting allopurinol during an attack of gout appears to be safe.<ref name=Rob2016>{{cite journal | vauthors = Robinson PC, Stamp LK | title = The management of gout: Much has changed | journal = Australian Family Physician | volume = 45 | issue = 5 | pages = 299–302 | date = May 2016 | pmid = 27166465 }}</ref><ref name="Satpanich">{{cite journal | vauthors = Satpanich P, Pongsittisak W, Manavathongchai S | title = Early versus Late Allopurinol Initiation in Acute Gout Flare (ELAG): a randomized controlled trial | journal = Clinical Rheumatology | volume = 41 | issue = 1 | pages = 213–221 | date = January 2022 | pmid = 34406530 | doi = 10.1007/s10067-021-05872-8 | ref = 6 | s2cid = 237156638 }}</ref> In those already on the medication, it should be continued even during an acute gout attack.<ref name=Rob2016/><ref name=WHO2008/> While use during [[pregnancy]] does not appear to result in harm, this use has not been well studied.<ref name="Drugs.com Pregnancy">{{cite web|title=Allopurinol Use During Pregnancy |url=https://www.drugs.com/pregnancy/allopurinol.html|website=Drugs.com|access-date=20 December 2016|url-status=live|archive-url=https://web.archive.org/web/20160820031050/https://www.drugs.com/pregnancy/allopurinol.html|archive-date=20 August 2016}}</ref> Allopurinol is in the [[xanthine oxidase inhibitor]] family of medications.<ref name=AHFS2016/>

<!-- Society and culture -->

Allopurinol was approved for medical use in the United States in 1966.<ref name=AHFS2016/> 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><ref name="WHO22nd">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 22nd list (2021) | year = 2021 | hdl = 10665/345533 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2021.02 | hdl-access=free }}</ref> Allopurinol is available as a [[generic medication]].<ref name=AHFS2016/> In 2021, it was the 40th most commonly prescribed medication in the United States, with more than 15{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2021 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=14 January 2024 | archive-date=15 January 2024 | archive-url=https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title=Allopurinol - Drug Usage Statistics | website=ClinCalc | url=https://clincalc.com/DrugStats/Drugs/Allopurinol | access-date=14 January 2024 | archive-date=13 April 2020 | archive-url=https://web.archive.org/web/20200413044027/https://clincalc.com/DrugStats/Drugs/Allopurinol | url-status=live }}</ref>

==Medical uses==

===Gout===

Allopurinol is used to reduce urate formation in conditions where urate deposition has already occurred or is predictable. The specific diseases and conditions where it is used include gouty arthritis, skin [[Tophus|tophi]], kidney stones, idiopathic gout; uric acid lithiasis; acute uric acid nephropathy; neoplastic disease and myeloproliferative disease with high cell turnover rates, in which high urate levels occur either spontaneously, or after cytotoxic therapy; certain enzyme disorders which lead to overproduction of urate, for example: [[hypoxanthine-guanine phosphoribosyltransferase]], including [[Lesch–Nyhan syndrome]]; [[glucose 6-phosphatase]] including [[glycogen storage disease]]; [[Ribose-phosphate diphosphokinase|phosphoribosyl pyrophosphate synthetase]], [[Amidophosphoribosyltransferase|phosphoribosyl pyrophosphate amidotransferase]]; [[adenine phosphoribosyltransferase]].

It is also used to treat kidney stones caused by deficient activity of [[adenine phosphoribosyltransferase]].

===Tumor lysis syndrome===

Allopurinol was also commonly used to treat [[tumor lysis syndrome]] in chemotherapeutic treatments, as these regimens can rapidly produce severe acute hyperuricemia;<ref name=Labeltablet/> however, it has gradually been replaced by [[urate oxidase]] therapy.<ref name="pmid11694945">{{cite journal | vauthors = Jeha S | title = Tumor lysis syndrome | journal = Seminars in Hematology | volume = 38 | issue = 4 Suppl 10 | pages = 4–8 | date = October 2001 | pmid = 11694945 | doi = 10.1016/S0037-1963(01)90037-X }}</ref> [[Intravenous therapy|Intravenous]] formulations are used in this indication when people are unable to swallow medication.<ref name=Labelinject/>

===Inflammatory bowel disease===

Allopurinol cotherapy is used to improve outcomes for people with [[inflammatory bowel disease]] and [[Crohn's disease]] who do not respond to thiopurine monotherapy.<ref name="pmid22072847">{{cite journal | vauthors = Bradford K, Shih DQ | title = Optimizing 6-mercaptopurine and azathioprine therapy in the management of inflammatory bowel disease | journal = World Journal of Gastroenterology | volume = 17 | issue = 37 | pages = 4166–73 | date = October 2011 | pmid = 22072847 | pmc = 3208360 | doi = 10.3748/wjg.v17.i37.4166 | doi-access = free }}</ref><ref name="pmid17296529">{{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 = 209–14 | date = February 2007 | pmid = 17296529 | doi = 10.1016/j.cgh.2006.11.020 | doi-access = free }}</ref> Cotherapy has also been shown to greatly improve hepatoxicity side effects in treatment of IBD.<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 = 640–7 | date = March 2010 | pmid = 20015102 | doi = 10.1111/j.1365-2036.2009.04221.x | s2cid = 6000856 | doi-access = free }}</ref> Cotherapy invariably requires dose reduction of the thiopurine, usually to one-third of the standard dose depending upon the patient's genetic status for [[thiopurine methyltransferase]].<ref name="autogenerated1">{{cite journal |vauthors=Ansari AR, Duley JA |title=Azathioprine co-therapy with allopurinol for inflammatory bowel disease: trials and tribulations |journal=Rev Assoc Med Bras |volume=58 |issue=Suppl.1 |pages=S28–33 |date=March 2012 |url=http://espace.library.uq.edu.au/view/UQ:272955/UQ272955_OA.pdf |access-date=11 September 2019 |archive-date=27 August 2021 |archive-url=https://web.archive.org/web/20210827211603/https://espace.library.uq.edu.au/data/UQ_272955/UQ272955_OA.pdf?Expires=1630099050&Key-Pair-Id=APKAJKNBJ4MJBJNC6NLQ&Signature=StZb8AymT78TToAwLa6m5u76KriWpn3mONCT~KNP9VeOWbG5MrhEcs7C-XShDxbPsiiesVIql-ZkY1Ju3zhTRzt23R5DOza2Jj6udGK9siG-i0VVnZlZ-6Jr0B7CbXAVP8poWb1bdz-13KAcisZQBUYlnJfIcYzNgeK5IBY3xACsMfXCtBWHViCto-p8NGMfiUn2VllxWpjZsdFh~JPK1Pyrx0cQOspWr6nuSF~FoOCvm2zy4W7Ogt6scKY~b7K2tVG23nuYGiEC8gLgoFRswU9I75GlzhgR6pTbmexxTJV--fVYubUNyOB22eloFZzG5NWlX2KYIwHFb17tRxaUnA__ |url-status=live }}</ref>

===Psychiatric disorders===

Allopurinol has been tested as an augmentation strategy for the treatment of [[mania]] in [[bipolar disorder]]. Meta-analytic evidence showed that adjunctive allopurinol was superior to placebo for acute mania (both with and without mixed features).<ref name="repurposed2021">{{cite journal | vauthors = Bartoli F, Cavaleri D, Bachi B, Moretti F, Riboldi I, Crocamo C, Carrà G | title = Repurposed drugs as adjunctive treatments for mania and bipolar depression: A meta-review and critical appraisal of meta-analyses of randomized placebo-controlled trials | journal = Journal of Psychiatric Research | date = September 2021 | volume = 143 | pages = 230–238 | doi = 10.1016/j.jpsychires.2021.09.018| pmid = 34509090 | s2cid = 237485915 }}</ref> Its efficacy was not influenced by dosage, follow-up duration, or concurrent standard treatment.<ref name="repurposed2021" />

=== Cardiovascular disease ===

There is a correlation between uric acid levels and cardiovascular disease and mortality, and so allopurinol has been explored as a potential treatment to reduce risk of cardiac disease.<ref>{{cite journal | vauthors = Kelkar A, Kuo A, Frishman WH | title = Allopurinol as a cardiovascular drug | journal = Cardiology in Review | volume = 19 | issue = 6 | pages = 265–271 | date = November 2011 | pmid = 21983313 | doi = 10.1097/CRD.0b013e318229a908 | s2cid = 7385203 }}</ref> However, the data is inconsistent and conflicting, and the use of allopurinol for use in cardiovascular disease is controversial. Independently of its effects on uric acid, it may also have effects on oxidative stress and inflammation.<ref>{{cite journal | vauthors = Connor M | title = Allopurinol for pain relief: more than just crystal clearance? | journal = British Journal of Pharmacology | volume = 156 | issue = 1 | pages = 4–6 | date = January 2009 | pmid = 19133987 | pmc = 2697767 | doi = 10.1111/j.1476-5381.2008.00065.x }}</ref>

== Side effects ==

Because allopurinol is not a [[uricosuric]], it can be used in people with poor [[kidney]] function. However, for people with impaired kidney function, allopurinol has two disadvantages. First, its dosing is complex.<ref name="pmid17897242">{{cite journal | vauthors = Dalbeth N, Stamp L | author-link1 = Nicola Dalbeth | title = Allopurinol dosing in renal impairment: walking the tightrope between adequate urate lowering and adverse events | journal = Seminars in Dialysis | volume = 20 | issue = 5 | pages = 391–5 | year = 2007 | pmid = 17897242 | doi = 10.1111/j.1525-139X.2007.00270.x | s2cid = 1150852 }}</ref> Second, some people are hypersensitive to the drug; therefore, its use requires careful monitoring.<ref name=Derm2016rev/><ref name="pmid20509717">{{cite journal | vauthors = Tsai TF, Yeh TY | title = Allopurinol in dermatology | journal = American Journal of Clinical Dermatology | volume = 11 | issue = 4 | pages = 225–32 | year = 2010 | pmid = 20509717 | doi = 10.2165/11533190-000000000-00000 | s2cid = 36847530 }}</ref>

Allopurinol has rare but potentially fatal adverse effects involving the skin. The most serious adverse effect is a hypersensitivity syndrome consisting of fever, skin rash, [[eosinophilia]], [[hepatitis]], and worsened renal function, collectively referred to as [[DRESS syndrome]].<ref name=Derm2016rev/> Allopurinol is one of the drugs commonly known to cause [[Stevens–Johnson syndrome]] and [[toxic epidermal necrolysis]], two life-threatening [[dermatology|dermatological]] conditions.<ref name=Derm2016rev/> More common is a less-serious rash that leads to discontinuing this drug.<ref name=Derm2016rev>{{cite journal | vauthors = Chung WH, Wang CW, Dao RL | title = Severe cutaneous adverse drug reactions | journal = The Journal of Dermatology | volume = 43 | issue = 7 | pages = 758–66 | date = July 2016 | pmid = 27154258 | doi = 10.1111/1346-8138.13430 | s2cid = 45524211 }}</ref>

More rarely, allopurinol can also result in the depression of bone marrow elements, leading to [[cytopenia]]s, as well as [[aplastic anemia]]. Moreover, allopurinol can also cause [[peripheral neuritis]] in some patients, although this is a rare side effect. Another side effect of allopurinol is [[interstitial nephritis]].<ref>{{cite book| vauthors = De Broe ME, Bennett WM, Porter GA |title=Clinical Nephrotoxins: Renal Injury from Drugs and Chemicals |url=https://books.google.com/books?id=sLM8F-IBgNcC&q=interstitial+nephritis+allopurinol&pg=PA317|year=2003|publisher=[[Springer Science+Business Media]]|quote=Acute interstitial nephritis has also been reported associated with by the administration of allopurinol.|isbn=9781402012778}}</ref>

==Drug interactions==

Drug interactions are extensive, and are as follows:<ref name=Labeltablet/>

* [[Azathioprine]] and [[6-mercaptopurine]]: Azathioprine is metabolised to 6-mercaptopurine which in turn is inactivated by the action of xanthine oxidase - the target of allopurinol. Giving allopurinol with either of these drugs at their normal dose will lead to overdose of either drug; only one-quarter of the usual dose of 6-mercaptopurine or azathioprine should be given;

* [[Didanosine]]: plasma didanosine Cmax and AUC values were approximately doubled with concomitant allopurinol treatment; it should not be co-administered with allopurinol and if it must be, the dose of should be reduced and the person should be closely monitored.

Allopurinol may also increase the activity or half-life of the following drugs, in order of seriousness and certainty of the interaction:<ref name=Labeltablet/>

* [[Ciclosporin]]

* [[Coumarin]] anticoagulants, such as [[warfarin]] (reported rarely, but is serious when it occurs)

* [[Vidarabine]]

* [[Chlorpropamide]]

* [[Phenytoin]]

* [[Theophylline]]

* [[Cyclophosphamide]], [[doxorubicin]], [[bleomycin]], [[procarbazine]], [[mechlorethamine]]

Co-administration of the following drugs may make allopurinol less active or decrease its half-life:<ref name=Labeltablet/>

* [[Salicylates]] and [[uricosuric|medicines that increase the secretion of uric acid]]

* [[furosemide]] (see more on diuretics below)

Co-administration of the following drugs may cause hypersensitivity or skin rash:<ref name=Labeltablet/>

* [[Ampicillin]] and [[amoxicillin]]

* [[Diuretics]], in particular thiazides, especially in renal impairment

* [[ACE inhibitors|Angiotensin-converting-enzyme inhibitors]] (ACE inhibitors)

[[File:Allopurinol.svg | thumb|220x124px | right]]

==Pharmacology==

A common misconception is that allopurinol is metabolized by its target, [[xanthine oxidase]], but this action is principally carried out by [[aldehyde oxidase]].<ref name="pmid2323062">{{cite journal | vauthors = Reiter S, Simmonds HA, Zöllner N, Braun SL, Knedel M | title = Demonstration of a combined deficiency of xanthine oxidase and aldehyde oxidase in xanthinuric patients not forming oxipurinol | journal = Clinica Chimica Acta; International Journal of Clinical Chemistry | volume = 187 | issue = 3 | pages = 221–34 | date = March 1990 | pmid = 2323062 | doi = 10.1016/0009-8981(90)90107-4 }}</ref> The active [[metabolite]] of allopurinol is [[oxipurinol]], which is also an inhibitor of xanthine oxidase. Allopurinol is almost completely metabolized to oxipurinol within two hours of oral administration, whereas oxipurinol is slowly excreted by the kidneys over 18–30 hours. For this reason, oxipurinol is believed responsible for the majority of allopurinol's effect.<ref name="pmid17655371">{{cite journal | vauthors = Day RO, Graham GG, Hicks M, McLachlan AJ, Stocker SL, Williams KM | title = Clinical pharmacokinetics and pharmacodynamics of allopurinol and oxypurinol | journal = Clinical Pharmacokinetics | volume = 46 | issue = 8 | pages = 623–44 | year = 2007 | pmid = 17655371 | doi = 10.2165/00003088-200746080-00001 | s2cid = 20369375 }}</ref>

=== Mechanism of action ===

Allopurinol is a purine analog; it is a structural [[isomer]] of [[hypoxanthine]] (a naturally occurring [[purine]] in the body) and is an [[enzyme inhibitor|inhibitor]] of the enzyme [[xanthine oxidase]].<ref name=Patcher2006rev/> Xanthine (1H-Purine-2,6-dione) oxidase is responsible for the successive oxidation of hypoxanthine to [[xanthine]] and subsequently [[uric acid]], the product of human purine metabolism.<ref name=Patcher2006rev/> In addition to blocking uric acid production, inhibition of xanthine oxidase causes an increase in hypoxanthine and xanthine. While xanthine cannot be converted to purine ribonucleotides, hypoxanthine can be salvaged to the purine [[ribotide|ribonucleotide]]s [[adenosine monophosphate|adenosine]] and [[guanosine monophosphate]]s. Increased levels of these ribonucleotides may cause feedback inhibition of [[amidophosphoribosyl transferase]], the first and rate-limiting enzyme of purine biosynthesis. Allopurinol, therefore, decreases uric acid formation and may also inhibit purine synthesis.<ref name="pmid8439471">{{cite journal | vauthors = Cameron JS, Moro F, Simmonds HA | title = Gout, uric acid and purine metabolism in paediatric nephrology | journal = Pediatric Nephrology | volume = 7 | issue = 1 | pages = 105–18 | date = February 1993 | pmid = 8439471 | doi = 10.1007/BF00861588 | s2cid = 34815040 }}</ref>

===Pharmacogenetics===

The HLA-B*5801 allele is a [[genetic marker]] for allopurinol-induced severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).<ref name="pharmgkb.org">{{cite web | title = Uric Acid-Lowering Drugs Pathway, Pharmacodynamics | work = PharmGKB | url = http://www.pharmgkb.org/haplotype/PA165956630#tabview=tab3&subtab= | archive-url = https://web.archive.org/web/20140808045855/http://www.pharmgkb.org/haplotype/PA165956630 | archive-date=8 August 2014 }}</ref><ref name="ReferenceA">{{cite web |url=http://www.pharmgkb.org/pathway/PA165980774 |title=PharmGKB |access-date=1 August 2014 |url-status=live |archive-url=https://web.archive.org/web/20140808045844/http://www.pharmgkb.org/pathway/PA165980774 |archive-date=8 August 2014 }}</ref> The frequency of the HLA-B*5801 allele varies between ethnicities: Han Chinese and Thai populations have HLA-B*5801 [[allele frequency|allele frequencies]] of around 8%, as compared to European and Japanese populations, who have allele frequencies of around 1.0% and 0.5%, respectively.<ref>{{cite web | title = Allele Frequency Net Database | url = http://www.allelefrequencies.net | archive-url = https://web.archive.org/web/20090828074156/http://www.allelefrequencies.net/ | archive-date=28 August 2009 }}</ref> The increase in risk for developing allopurinol-induced SJS or TEN in individuals with the HLA-B*5801 allele (as compared to those who do not have this allele) is very high, ranging from a 40-fold to a 580-fold increase in risk, depending on ethnicity.<ref name="pharmgkb.org"/><ref name="ReferenceA"/> As of 2011 the FDA-approved drug label for allopurinol did not contain any information regarding the HLA-B*5801 allele, though FDA scientists did publish a study in 2011 which reported a strong, reproducible and consistent association between the allele and allopurinol-induced SJS and TEN.<ref>{{cite journal | vauthors = Zineh I, Mummaneni P, Lyndly J, Amur S, La Grenade LA, Chang SH, Rogers H, Pacanowski MA | title = Allopurinol pharmacogenetics: assessment of potential clinical usefulness | journal = Pharmacogenomics | volume = 12 | issue = 12 | pages = 1741–9 | date = December 2011 | pmid = 22118056 | doi = 10.2217/pgs.11.131 | url = https://zenodo.org/record/1236437 | access-date = 3 June 2020 | archive-date = 27 August 2021 | archive-url = https://web.archive.org/web/20210827211602/https://zenodo.org/record/1236437/preview/article.pdf | url-status = live }}</ref> However, the American College of Rheumatology recommends screening for HLA-B*5801 in high-risk populations (''e.g.'' Koreans with stage 3 or worse chronic kidney disease and those of Han Chinese and Thai descent), and prescribing patients who are positive for the allele an alternative drug.<ref>{{cite journal | vauthors = Khanna D, Fitzgerald JD, Khanna PP, Bae S, Singh MK, Neogi T, Pillinger MH, Merill J, Lee S, Prakash S, Kaldas M, Gogia M, Perez-Ruiz F, Taylor W, Lioté F, Choi H, Singh JA, Dalbeth N, Kaplan S, Niyyar V, Jones D, Yarows SA, Roessler B, Kerr G, King C, Levy G, Furst DE, Edwards NL, Mandell B, Schumacher HR, Robbins M, Wenger N, Terkeltaub R | title = 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia | journal = Arthritis Care & Research | volume = 64 | issue = 10 | pages = 1431–46 | date = October 2012 | pmid = 23024028 | pmc = 3683400 | doi = 10.1002/acr.21772 }}</ref> The Clinical Pharmacogenetics Implementation Consortium (CPIC)<ref>{{cite web |date=27 November 2023 |title=CPIC |url=https://cpicpgx.org/ |access-date=10 December 2023 |archive-date=1 July 2023 |archive-url=https://web.archive.org/web/20230701123758/https://cpicpgx.org/ |url-status=live }}</ref> guidelines state that allopurinol is contraindicated in known carriers of the HLA-B*5801 allele.<ref>{{cite web |url=http://www.pharmgkb.org/guideline/PA166105003 |work = PharmGKB | title = Annotation of CPIC Guideline for allopurinol and HLA-B |access-date=1 August 2014 |url-status=live |archive-url= https://web.archive.org/web/20140808045834/http://www.pharmgkb.org/guideline/PA166105003 |archive-date=8 August 2014 }}</ref><ref>{{cite journal | vauthors = Hershfield MS, Callaghan JT, Tassaneeyakul W, Mushiroda T, Thorn CF, Klein TE, Lee MT | title = Clinical Pharmacogenetics Implementation Consortium guidelines for human leukocyte antigen-B genotype and allopurinol dosing | journal = Clinical Pharmacology and Therapeutics | volume = 93 | issue = 2 | pages = 153–8 | date = February 2013 | pmid = 23232549 | pmc = 3564416 | doi = 10.1038/clpt.2012.209 }}</ref>

== History ==

Allopurinol was first synthesized and reported in 1956 by Roland K. Robins (1926–1992), in a search for [[Alkylating antineoplastic agent|antineoplastic agents]].<ref name=Patcher2006rev/><ref>{{cite journal | vauthors = Robins RK | journal = Journal of the American Chemical Society | volume = 78 | pages = 784–790 | date = February 1956 | doi = 10.1021/ja01585a023 | title = Potential Purine Antagonists. I. Synthesis of Some 4,6-Substituted Pyrazolo [3,4-d] pyrimidines | issue = 4}}</ref> Allopurinol inhibits the breakdown ([[catabolism]]) of the [[thiopurine]] drug [[mercaptopurine]], and was later tested by Wayne Rundles in collaboration with [[Gertrude Elion]]'s lab at [[Wellcome Research Laboratories]] to see if it could improve treatment of [[acute lymphoblastic leukemia]] by enhancing the action of mercaptopurine.<ref name=Patcher2006rev/><ref name=Sneader>{{cite book | vauthors = Sneader W | title = Drug Discovery: A History. | publisher = John Wiley & Sons | date = 2005 | isbn = 9780471899792 | url = https://books.google.com/books?id=Cb6BOkj9fK4C&pg=PA254 | page = 254 | access-date = 4 September 2015 | archive-date = 14 January 2023 | archive-url = https://web.archive.org/web/20230114105733/https://books.google.com/books?id=Cb6BOkj9fK4C&pg=PA254 | url-status = live }}</ref> However, no improvement in leukemia response was noted with mercaptopurine-allopurinol co-therapy, so that work turned to other compounds and the team then started testing allopurinol as a potential therapeutic for gout.<ref name="pmid2649979">{{cite journal | vauthors = Elion GB | title = The purine path to chemotherapy | journal = Science | volume = 244 | issue = 4900 | pages = 41–7 | date = April 1989 | pmid = 2649979 | doi = 10.1126/science.2649979 | bibcode = 1989Sci...244...41E }}</ref> Allopurinol was first marketed as a treatment for gout in 1966.<ref name=Sneader/>

==Society and culture==

[[File:Allopurinol substance photo.jpg|thumb|Pure allopurinol is a white powder.]]

===Formulations===

Allopurinol is sold as an injection for intravenous use<ref name=Labelinject>{{cite web | work = DailyMed | url = https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=10cc918f-aa44-415b-932d-2404695ac449 | title = Label for injectable Allopurinol | archive-url = https://web.archive.org/web/20160913084333/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=10cc918f-aa44-415b-932d-2404695ac449 | archive-date=13 September 2016 | date = June 2014 }}</ref> and as a tablet.<ref name=Labeltablet>{{cite web | work = UK Electronic Medicines Compendium | url = https://www.medicines.org.uk/emc/medicine/25728 | title = 300 mg Allopurinol tables | archive-url = https://web.archive.org/web/20160911024141/https://www.medicines.org.uk/emc/medicine/25728 | archive-date=11 September 2016 | date = 7 April 2016 }}</ref>

===Brands===

[[File:Milurit 100mg allopurinolum.jpg|thumb|upright=0.6|A package of Milurit 100mg (a brand of allopurinol)]]

Allopurinol has been marketed in the United States since 19 August 1966, when it was first approved by FDA under the trade name Zyloprim.<ref>{{cite web |url=http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm |work = Drugs@FDA | title = FDA Approved Drug Products |access-date=8 November 2013 |url-status=live |archive-url=https://web.archive.org/web/20120814072104/http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA/index.cfm |archive-date=14 August 2012 }}</ref> Allopurinol was marketed at the time by [[Burroughs Wellcome]]. Allopurinol is a generic drug sold under a variety of brand names, including Allohexal, Allosig, Milurit, Alloril, Progout, Ürikoliz, Zyloprim, Zyloric, Zyrik, and Aluron.<ref>{{cite web |url=http://dailymed.nlm.nih.gov/dailymed/search.cfm?startswith=Allopurinol&x=0&y=0 |work = DailyMed | title = Search Results for Allopurinol |access-date=27 July 2011 |url-status=live |archive-url=https://web.archive.org/web/20120325001706/http://dailymed.nlm.nih.gov/dailymed/search.cfm?startswith=Allopurinol&x=0&y=0 |archive-date=25 March 2012 }}</ref>

== See also ==

* [[Lesinurad/allopurinol]], a fixed-dose combination drug

== References ==

{{reflist}}

== Further reading ==

* {{cite book | title=Medical Genetics Summaries | chapter=Allopurinol Therapy and HLA-B*58:01 Genotype | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK127547/ | veditors=Pratt VM, McLeod HL, Rubinstein WS, Scott SA, Dean LC, Kattman BL, Malheiro AJ | display-editors=6 | publisher=[[National Center for Biotechnology Information]] (NCBI) | date=March 2016 | pmid=28520356 | vauthors=Dean L | url=https://www.ncbi.nlm.nih.gov/books/NBK61999/ }}

== External links ==

* [http://www.pharmgkb.org/pathway/PA165980774 Allopurinol pathway on PharmGKB]

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