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| Trade names | Zyloprim, Caplenal, Zyloric, others |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a682673 |
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| Routes of administration | Oral,intravenous |
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| Pharmacokinetic data | |
| Bioavailability | 78±20% |
| Protein binding | Negligible |
| Metabolism | Liver (80%oxipurinol, 10% allopurinol ribosides) |
| Eliminationhalf-life | 2 h (oxipurinol 18–30 h) |
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| ECHA InfoCard | 100.005.684 |
| Chemical and physical data | |
| Formula | C5H4N4O |
| Molar mass | 136.114 g·mol−1 |
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Allopurinol is amedication used to decreasehigh blood uric acid levels.[5] It is specifically used to preventgout, prevent specific types ofkidney stones and for the high uric acid levels that can occur withchemotherapy.[6][7] It is takenorally (by mouth) orintravenously (injected into a vein).[7]
Common side effects when used orally include itchiness and rash.[7] Common side effects when used by injection includevomiting andkidney problems.[7] While not recommended historically, starting allopurinol during an attack of gout appears to be safe.[8][9] In those already on the medication, it should be continued even during an acute gout attack.[8][6] While use duringpregnancy does not appear to result in harm, this use has not been well studied.[1] Allopurinol is in thexanthine oxidase inhibitor family of medications.[7]
Allopurinol was approved for medical use in the United States in 1966.[7] It is on theWorld Health Organization's List of Essential Medicines.[10] Allopurinol is available as ageneric medication.[7] In 2023, it was the 45th most commonly prescribed medication in the United States, with more than 14 million prescriptions.[11][12]
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, skintophi, 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, includingLesch–Nyhan syndrome;glucose 6-phosphatase includingglycogen storage disease;phosphoribosyl pyrophosphate synthetase,phosphoribosyl pyrophosphate amidotransferase;adenine phosphoribosyltransferase.
It is also used to treat kidney stones caused by deficient activity ofadenine phosphoribosyltransferase.
Allopurinol was also commonly used to treattumor lysis syndrome in chemotherapeutic treatments, as these regimens can rapidly produce severe acute hyperuricemia;[13] however, it has gradually been replaced byurate oxidase therapy.[14]Intravenous formulations are used in this indication when people are unable to swallow medication.[4]
Allopurinol cotherapy is used to improve outcomes for people withinflammatory bowel disease andCrohn's disease who do not respond to thiopurine monotherapy.[15][16] Cotherapy has also been shown to greatly improve hepatoxicity side effects in treatment of IBD.[17] Cotherapy invariably requires dose reduction of the thiopurine, usually to one-third of the standard dose depending upon the patient's genetic status forthiopurine methyltransferase.[18]
Allopurinol has been tested as an augmentation strategy for the treatment ofmania inbipolar disorder. Meta-analytic evidence showed that adjunctive allopurinol was superior to placebo for acute mania (both with and without mixed features).[19] Its efficacy was not influenced by dosage, follow-up duration, or concurrent standard treatment.[19]
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.[20] 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 onoxidative stress and inflammation.[21]
Allopurinol is commonly used in the veterinary treatment ofleishmaniosis.[22][23]
Because allopurinol is not auricosuric, it can be used in people with poorkidney function. However, for people with impaired kidney function, allopurinol has two disadvantages. First, its dosing is complex.[24] Second, some people are hypersensitive to the drug; therefore, its use requires careful monitoring.[25][26]
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 asDRESS syndrome.[25] Allopurinol is one of the drugs commonly known to causeStevens–Johnson syndrome andtoxic epidermal necrolysis, two life-threateningdermatological conditions.[25] More common is a less-serious rash that leads to discontinuing this drug.[25]
More rarely, allopurinol can also result in the depression of bone marrow elements, leading tocytopenias, as well asaplastic anemia. Moreover, allopurinol can also causeperipheral neuritis in some patients, although this is a rare side effect. Another side effect of allopurinol isinterstitial nephritis.[27]
Drug interactions are extensive, and are as follows:[13]
Allopurinol may also increase the activity or half-life of the following drugs, in order of seriousness and certainty of the interaction:[13]
Co-administration of the following drugs may make allopurinol less active or decrease its half-life:[13]
Co-administration of the following drugs may cause hypersensitivity or skin rash:[13]
A common misconception is that allopurinol is metabolized by its target,xanthine oxidase, but this action is principally carried out byaldehyde oxidase.[28] The activemetabolite of allopurinol isoxipurinol, 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.[29]
Allopurinol is a purine analog; it is a structuralisomer ofhypoxanthine (a naturally occurringpurine in the body) and is aninhibitor of the enzymexanthine oxidase.[5] Xanthine (1H-Purine-2,6-dione) oxidase is responsible for the successive oxidation of hypoxanthine toxanthine and subsequentlyuric acid, the product of human purine metabolism.[5] 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 purineribonucleotidesadenosine andguanosine monophosphates. Increased levels of these ribonucleotides may cause feedback inhibition ofamidophosphoribosyl transferase, the first and rate-limiting enzyme of purine biosynthesis. Allopurinol, therefore, decreases uric acid formation and may also inhibit purine synthesis.[30]
The HLA-B*5801 allele is agenetic marker for allopurinol-induced severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).[31][32] The frequency of the HLA-B*5801 allele varies between ethnicities: Han Chinese and Thai populations have HLA-B*5801allele frequencies of around 8%, as compared to European and Japanese populations, who have allele frequencies of around 1.0% and 0.5%, respectively.[33] 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.[31][32] 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.[34] 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.[35] The Clinical Pharmacogenetics Implementation Consortium (CPIC)[36] guidelines state that allopurinol is contraindicated in known carriers of the HLA-B*5801 allele.[37][38]
Allopurinol was first synthesized and reported in 1956 by Roland K. Robins (1926–1992), in a search forantineoplastic agents.[5][39] Allopurinol inhibits the breakdown (catabolism) of thethiopurine drugmercaptopurine, and was later tested by Wayne Rundles in collaboration withGertrude Elion's lab atWellcome Research Laboratories to see if it could improve treatment ofacute lymphoblastic leukemia by enhancing the action of mercaptopurine.[5][40] 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.[41] Allopurinol was first marketed as a treatment for gout in 1966.[40]
Allopurinol is sold as an injection for intravenous use[4] and as a tablet.[13]
Allopurinol has been marketed in the United States since 19 August 1966, when it was first approved by FDA under the trade name Zyloprim.[42] Allopurinol was marketed at the time byBurroughs 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.[43]
Acute interstitial nephritis has also been reported associated with by the administration of allopurinol.
