Editing Azathioprine (section)

===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>