Fluorouracil

{{Short description|Chemotherapy medication}} {{Use dmy dates|date=August 2025}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox drug | Watchedfields = changed | verifiedrevid = 456480929 | image = Fluorouracil2DACS.svg | image_class = skin-invert-image | width = 80 | alt = | image2 = Fluorouracil-from-xtal-3D-bs-17.png | image_class2 = bg-transparent | width2 = 100 | alt2 =

| pronounce = {{IPAc-en|ˌ|f|l|ʊər|oʊ|ˈ|j|ʊər|ə|s|ɪ|l}}<ref>{{cite web |title=Fluorouracil – Definition and More from the Free Merriam-Webster Dictionary |url=http://www.merriam-webster.com/dictionary/fluorouracil |access-date=19 November 2014 |url-status=live |archive-url=https://web.archive.org/web/20141129194245/http://www.merriam-webster.com/dictionary/fluorouracil |archive-date=29 November 2014 }}</ref> | tradename = Adrucil, others | Drugs.com = {{drugs.com|monograph|fluorouracil}} | MedlinePlus = a682708 | DailyMedID = Fluorouracil | pregnancy_AU = D | pregnancy_category = | routes_of_administration = Intravenous, topical | ATC_prefix = L01 | ATC_suffix = BC02 | ATC_supplemental = {{ATC|L01|BC52}}

| legal_AU = S4 | legal_CA = Rx-only | legal_CA_comment = <ref>{{cite web|url=https://pdf.hres.ca/dpd_pm/00049486.PDF|title=TOLAK : Fluorouracil Cream: 4% (w/w) fluorouracil (as fluorouracil sodium)|website=Pdf.hres.ca|access-date=8 June 2022|archive-date=10 June 2022|archive-url=https://web.archive.org/web/20220610030126/https://pdf.hres.ca/dpd_pm/00049486.PDF|url-status=live}}</ref> | legal_UK = POM | legal_US = Rx-only

| IUPHAR_ligand = 4789 | CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 51-21-8 | PubChem = 3385 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB00544 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 3268 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = U3P01618RT | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D00584 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 46345 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 185

| IUPAC_name = 5-Fluoro-1''H'',3''H''-pyrimidine-2,4-dione | C=4 | H=3 | F=1 | N=2 | O=2 | smiles = O=C1NC(=O)NC=C1F | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C4H3FN2O2/c5-2-1-6-4(9)7-3(2)8/h1H,(H2,6,7,8,9) | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = GHASVSINZRGABV-UHFFFAOYSA-N | melting_point = 282–283 }}  '''Fluorouracil''' ('''5-FU''', '''5-fluorouracil'''), sold under the brand name '''Adrucil''' among others, is a cytotoxic chemotherapy medication used to treat cancer.<ref name=AHFS2016/> By intravenous injection it is used for treatment of colorectal cancer, oesophageal cancer, stomach cancer, pancreatic cancer, breast cancer, and cervical cancer.<ref name=AHFS2016>{{cite web|title=Fluorouracil|url=https://www.drugs.com/monograph/fluorouracil.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161220192631/https://www.drugs.com/monograph/fluorouracil.html|archive-date=20 December 2016}}</ref> As a cream it is used for actinic keratosis, basal cell carcinoma, and skin warts.<ref name=AHFS2016Top>{{cite web|title=Fluorouracil topical|url=https://www.drugs.com/monograph/fluorouracil-topical.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161226054457/https://www.drugs.com/monograph/fluorouracil-topical.html|archive-date=26 December 2016}}</ref><ref>{{cite journal | vauthors = Moore AY | title = Clinical applications for topical 5-fluorouracil in the treatment of dermatological disorders | journal = The Journal of Dermatological Treatment | volume = 20 | issue = 6 | pages = 328–335 | date = 2009 | pmid = 19954388 | doi = 10.3109/09546630902789326 }}</ref>

Side effects of use by injection are common.<ref name=AHFS2016/> They may include inflammation of the mouth, loss of appetite, low blood cell counts, hair loss, and inflammation of the skin.<ref name=AHFS2016/> When used as a cream, irritation at the site of application usually occurs.<ref name=AHFS2016Top/> Use of either form in pregnancy may harm the fetus.<ref name=AHFS2016/> Fluorouracil is in the antimetabolite and pyrimidine analog families of medications.<ref name=BNF69>{{cite book|title=British national formulary: BNF 69|date=2015|publisher=British Medical Association|isbn=978-0-85711-156-2|page=590|edition=69}}</ref><ref>{{cite book| vauthors = Airley R |title=Cancer Chemotherapy: Basic Science to the Clinic|date=2009|publisher=John Wiley & Sons|isbn=978-0-470-09256-9|page=76|url=https://books.google.com/books?id=wjjYyYpfiQ8C&pg=PA76|language=en|url-status=live|archive-url=https://web.archive.org/web/20171105200744/https://books.google.com/books?id=wjjYyYpfiQ8C&pg=PA76|archive-date=5 November 2017}}</ref> How it works is not entirely clear, but it is believed to involve blocking the action of thymidylate synthase and thus stopping the production of DNA.<ref name=AHFS2016/>

Fluorouracil was patented in 1956 and came into medical use in 1962.<ref name=Fis2006>{{cite book| vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery|date=2006|publisher=John Wiley & Sons|isbn=978-3-527-60749-5|page=511|url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA511|language=en|url-status=live|archive-url=https://web.archive.org/web/20170911002644/https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA511|archive-date=11 September 2017}}</ref> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO23rd">{{cite book | vauthors = ((World Health Organization)) | title = The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) | year = 2023 | hdl = 10665/371090 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2023.02 | hdl-access=free }}</ref> In 2023, it was the 267th most commonly prescribed medication in the United States, with more than 900,000 prescriptions.<ref>{{cite web | title=The Top 300 of 2023 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=17 August 2025 | archive-date=17 August 2025 | archive-url=https://web.archive.org/web/20250817043812/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Fluorouracil Drug Usage Statistics, United States, 2014 - 2023 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Fluorouracil | access-date = 17 August 2025 }}</ref>

==Medical uses== {{Multiple image | perrow = 1 | total_width = 200 | direction = vertical | image1 = Efudix immediately post-treatment.jpg | width1 = 190px | alt1 = Male forearm showing oval scabbed skin patch with scales and reddening | caption1 = Effect of topical skin treatment with 5-fluorouracil cream after a standard 30-day treatment, before commencement of the healing phase (months two and three) | image2 = Efudix effect three plus years post-treatment.jpg | width2 = 190px | alt2 = Male forearm showing healed skin with a creamy, shiny patch having pigmentation loss | caption2 = Healed skin three+ years after treatment, showing some pigmentation loss }} Fluorouracil has been given systemically for anal, breast, colorectal, oesophageal, stomach, pancreatic and skin cancers (especially head and neck cancers).<ref name="AMH">{{cite book | veditors = Rossi S | isbn = 978-0-9805790-9-3 | title = Australian Medicines Handbook | place = Adelaide | publisher = The Australian Medicines Handbook Unit Trust | year = 2013 | edition = 2013 }}</ref> It has also been given topically (on the skin) for actinic keratosis, skin cancers and Bowen's disease<ref name = AMH/> (a type of cutaneous squamous-cell carcinoma), and as eye drops for treatment of ocular surface squamous neoplasia.<ref>{{cite journal | vauthors = Joag MG, Sise A, Murillo JC, Sayed-Ahmed IO, Wong JR, Mercado C, Galor A, Karp CL | title = Topical 5-Fluorouracil 1% as Primary Treatment for Ocular Surface Squamous Neoplasia | journal = Ophthalmology | volume = 123 | issue = 7 | pages = 1442–1448 | date = July 2016 | pmid = 27030104 | pmc = 4921289 | doi = 10.1016/j.ophtha.2016.02.034 }}</ref> Other uses include ocular injections into a previously created trabeculectomy bleb to inhibit healing and cause scarring of tissue, thus allowing adequate aqueous humor flow to reduce intraocular pressure.

5-Fluorouracil has application in the synthesis of fostamatinib.

==Contraindications== Fluorouracil is contraindicated in patients who are severely debilitated and in patients with bone marrow suppression due to either radiotherapy or chemotherapy.<ref name = EMC/> It is likewise contraindicated in pregnant or breastfeeding women.<ref name = EMC/>

Non-topical use, i.e. administration by injection, should be avoided in patients who do not have malignant illnesses.<ref name="EMC" />

In 2020, the EU and UK license was updated to state that fluorouracil was contra-indicated in patients that "have a known complete absence of dihydropyrimidine dehydrogenase (DPD) activity".<ref>{{Cite web |title=Fluorouracil 50 mg/ml Injection - Summary of Product Characteristics (SmPC) - (emc) |url=https://www.medicines.org.uk/emc/product/3791/smpc |access-date=26 December 2024 |website=www.medicines.org.uk}}</ref> In US, as of 2024, there is no specific contraindication on the package inserts however, there is a cautionary warning: "Increased risk of serious or fatal adverse reactions in patients with low or absent Dipyrimidine Dehydrogenase activity: withhold or permanently discontinue fluorouracil in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of dipyrimidine dehydrogenase (DPD) activity.

No fluorouracil dose has been proven safe in patients with absent DPD activity."<ref name=":0">{{Cite web |title=Drugs@FDA: FDA-Approved Drugs |url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=012209 |access-date=26 December 2024 |website=www.accessdata.fda.gov |language=en}}</ref>

Within the UK, DPYD testing to check for this contraindication is now routine practice;<ref>{{Cite web | vauthors = Robinson J |date=5 May 2022 |title=Cancer pharmacogenomics testing: are we hitting the mark? |url=https://pharmaceutical-journal.com/article/feature/cancer-pharmacogenomics-testing-are-we-hitting-the-mark |access-date=26 December 2024 |website=The Pharmaceutical Journal |language=en-US}}</ref> this is not the case in the US.<ref>{{cite journal | vauthors = Koo K, Pasternak AL, Henry NL, Sahai V, Hertz DL | title = Survey of US Medical Oncologists' Practices and Beliefs Regarding ''DPYD'' Testing Before Fluoropyrimidine Chemotherapy | journal = JCO Oncology Practice | volume = 18 | issue = 6 | pages = e958–e965 | date = June 2022 | pmid = 35239419 | pmc = 9191302 | doi = 10.1200/OP.21.00874 }}</ref>

==Adverse effects== Adverse effects by frequency include:<ref name = AMH/><ref name=EMC>{{cite web|title=Fluorouracil 50 mg/ml Injection – Summary of Product Characteristics|work=electronic Medicines Compendium|publisher=Hospira UK Ltd|date=24 August 2011|access-date=24 January 2014|url=http://www.medicines.org.uk/emc/medicine/636/SPC/Fluorouracil++50+mg+ml++Injection/|url-status=live|archive-url=https://web.archive.org/web/20140201204538/http://www.medicines.org.uk/emc/medicine/636/SPC/Fluorouracil++50+mg+ml++Injection/|archive-date=1 February 2014}}</ref><ref name=TGA>{{cite web|title=DBL Fluorouracil Injection BP|work=TGA eBusiness Services|publisher=Hospira Australia Pty Ltd|date=21 June 2012|access-date=24 January 2014|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2011-PI-02952-3|format=PDF|url-status=live|archive-url=https://web.archive.org/web/20170128034658/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2011-PI-02952-3|archive-date=28 January 2017}}</ref><ref name=DM>{{cite web|title=ADRUCIL (fluorouracil) injection [Teva Parenteral Medicines, Inc.]|work=DailyMed|publisher=Teva Parenteral Medicines, Inc.|date=August 2012|access-date=24 January 2014|url=https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=b90e0da7-f702-4f09-9488-74f2bb20e9ac|url-status=live|archive-url=https://web.archive.org/web/20140201231133/http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=b90e0da7-f702-4f09-9488-74f2bb20e9ac|archive-date=1 February 2014}}</ref><ref name=MSRIV>{{cite web|title=Adrucil (fluorouracil) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=24 January 2014|url=http://reference.medscape.com/drug/adrucil-fluorouracil-342092#showall|url-status=live|archive-url=https://web.archive.org/web/20140202174903/http://reference.medscape.com/drug/adrucil-fluorouracil-342092#showall|archive-date=2 February 2014}}</ref>

===During systemic use=== Common (> 1% frequency):{{div col|colwidth=18em}} * Nausea * Vomiting * Diarrhea (see below for details) * Mucositis * Headache * Hand-foot syndrome * Myelosuppression (see below for details) * Alopecia (hair loss) * Photosensitivity * Maculopapular eruption * Itch * Cardiotoxicity (see below for details) * Persistent hiccups<ref>{{cite web | url = http://medsfacts.com/study-5FU%28FLUOROURACIL%29-causing-HICCUPS.php | work = MedsFacts | title = Meta-analysis covering adverse side effect reports of 5fu(fluorouracil) patients who developed hiccups | archive-url = https://web.archive.org/web/20140905143353/http://medsfacts.com/study-5FU%28FLUOROURACIL%29-causing-HICCUPS.php | archive-date=5 September 2014 }}</ref> * Mood disorders (irritability, anxiety, depression) {{div col end}}

Uncommon (0.1–1% frequency): {{div col|colwidth=18em}} * Oesophagitis * GI ulceration and bleeding * Proctitis * Nail disorders * Vein pigmentation * Confusion * Cerebellar syndrome * Encephalopathy * Visual changes * Photophobia * Lacrimation (the expulsion of tears without any emotional or physiologic reason) {{div col end}}

Rare (< 0.1% frequency): * Anaphylaxis * Allergic reactions * Fever without signs of infection * Mania, reversible dementia<ref>{{cite journal | vauthors = Ha JH, Hwang DY, Yu J, Park DH, Ryu SH | title = Onset of Manic Episode during Chemotherapy with 5-Fluorouracil | journal = Psychiatry Investigation | volume = 8 | issue = 1 | pages = 71–73 | date = March 2011 | pmid = 21519541 | pmc = 3079190 | doi = 10.4306/pi.2011.8.1.71 }}</ref><ref>Park H. J., Choi Y. T., Kim I. H., Hah J. C.; A case of reversible dementia associated with depression in a patient on 5-FU or its analogue drugs. J. Korean Neuropsychiatr. Assoc. 1987;30:199–202.</ref>

Diarrhea is severe and may be dose-limiting and is exacerbated by co-treatment with calcium folinate.<ref name = AMH/> Neutropenia tends to peak about 9–14 days after beginning treatment.<ref name = AMH/> Thrombocytopenia tends to peak about 7–17 days after the beginning of treatment and tends to recover about 10 days after its peak.<ref name = AMH/> Cardiotoxicity is a fairly common side effect, usually manifesting as angina or symptoms associated with coronary artery spasm, but about 0.55% of those receiving the drug will develop life-threatening cardiotoxicity.<ref name="MD">{{cite web|title=Fluorouracil: Martindale: The Complete Drug Reference|date=9 January 2017|url=https://www.medicinescomplete.com/mc/martindale/current/1836-x.htm|access-date=14 August 2017| veditors = Brayfield A |publisher=Pharmaceutical Press|website=MedicinesComplete|location=London, UK|archive-date=28 August 2021|archive-url=https://web.archive.org/web/20210828090019/https://about.medicinescomplete.com/wp-content/plugins/revslider/public/assets/js/extensions/revolution.extension.slideanims.min.js?version=5.4.5|url-status=live}}</ref> Life-threatening cardiotoxicity includes: arrhythmias, ventricular tachycardia and cardiac arrest, secondary to transmural ischaemia.<ref name="MD"/>

===During topical use=== Common (> 1% frequency):<ref name = AMH/><ref name=MSRT>{{cite web|title=Efudex, Carac (fluorouracil topical) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=24 January 2014|url=http://reference.medscape.com/drug/efudex-carac-fluorouracil-topical-343545#showall|url-status=live|archive-url=https://web.archive.org/web/20140202174906/http://reference.medscape.com/drug/efudex-carac-fluorouracil-topical-343545#showall|archive-date=2 February 2014}}</ref> {{div col|colwidth=18em}} * Local pain * Itchiness * Burning * Stinging * Crusting * Weeping * Dermatitis * Photosensitivity {{div col end}}

Uncommon (0.1–1% frequency): * Hyper- or hypopigmentation * Scarring

===Neurological damage=== The United States package insert warns that acute cerebellar syndrome has been observed following injection of fluorouracil and may persist after cessation of treatment. Symptoms include ataxia, nystagmus, and dysmetria.<ref>{{cite web|url=https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=e0794add-67a7-4308-93e9-f889472716cc|title=Adrucil (Fluorouracil) Injection [TEVA Parenteral Medicines, Inc.]|url-status=live|archive-url=https://web.archive.org/web/20140814024152/http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=e0794add-67a7-4308-93e9-f889472716cc|archive-date=14 August 2014}}</ref>

==Potential overdose== There is very little difference between the minimum effective dose and maximum tolerated dose of 5-FU, and the drug exhibits marked individual pharmacokinetic variability.<ref name="dose monitoring">{{cite journal | vauthors = Gamelin E, Boisdron-Celle M | title = Dose monitoring of 5-fluorouracil in patients with colorectal or head and neck cancer--status of the art | journal = Critical Reviews in Oncology/Hematology | volume = 30 | issue = 1 | pages = 71–79 | date = March 1999 | pmid = 10439055 | doi = 10.1016/s1040-8428(98)00036-5 }}</ref><ref name="dosing strategies">{{cite journal | vauthors = Felici A, Verweij J, Sparreboom A | title = Dosing strategies for anticancer drugs: the good, the bad and body-surface area | journal = European Journal of Cancer | volume = 38 | issue = 13 | pages = 1677–1684 | date = September 2002 | pmid = 12175683 | doi = 10.1016/s0959-8049(02)00151-x }}</ref><ref name="role of body">{{cite journal | vauthors = Baker SD, Verweij J, Rowinsky EK, Donehower RC, Schellens JH, Grochow LB, Sparreboom A | title = Role of body surface area in dosing of investigational anticancer agents in adults, 1991-2001 | journal = Journal of the National Cancer Institute | volume = 94 | issue = 24 | pages = 1883–1888 | date = December 2002 | pmid = 12488482 | doi = 10.1093/jnci/94.24.1883 | doi-access = free }}</ref> Therefore, an identical dose of 5-FU may result in a therapeutic response with acceptable toxicity in some patients and unacceptable and possibly life-threatening toxicity in others.<ref name="dose monitoring"/> Both overdosing and underdosing are of concern with 5-FU, although several studies have shown that the majority of colorectal cancer patients treated with 5-FU are underdosed based on today's dosing standard, body surface area (BSA).<ref name="dose adjustment">{{cite journal | vauthors = Capitain O, Asevoaia A, Boisdron-Celle M, Poirier AL, Morel A, Gamelin E | title = Individual fluorouracil dose adjustment in FOLFOX based on pharmacokinetic follow-up compared with conventional body-area-surface dosing: a phase II, proof-of-concept study | journal = Clinical Colorectal Cancer | volume = 11 | issue = 4 | pages = 263–267 | date = December 2012 | pmid = 22683364 | doi = 10.1016/j.clcc.2012.05.004 }}</ref><ref name="body surface area">{{cite journal | vauthors = Saam J, Critchfield GC, Hamilton SA, Roa BB, Wenstrup RJ, Kaldate RR | title = Body surface area-based dosing of 5-fluoruracil results in extensive interindividual variability in 5-fluorouracil exposure in colorectal cancer patients on FOLFOX regimens | journal = Clinical Colorectal Cancer | volume = 10 | issue = 3 | pages = 203–206 | date = September 2011 | pmid = 21855044 | doi = 10.1016/j.clcc.2011.03.015 }}</ref><ref name="multicenter evaluation">{{cite journal | vauthors = Beumer JH, Boisdron-Celle M, Clarke W, Courtney JB, Egorin MJ, Gamelin E, Harney RL, Hammett-Stabler C, Lepp S, Li Y, Lundell GD, McMillin G, Milano G, Salamone SJ | title = Multicenter evaluation of a novel nanoparticle immunoassay for 5-fluorouracil on the Olympus AU400 analyzer | journal = Therapeutic Drug Monitoring | volume = 31 | issue = 6 | pages = 688–694 | date = December 2009 | pmid = 19935361 | doi = 10.1097/FTD.0b013e3181b9b8c0 }}</ref><ref>{{cite journal | vauthors = Goldberg RM, Rothenberg ML, Van Cutsem E, Benson AB, Blanke CD, Diasio RB, Grothey A, Lenz HJ, Meropol NJ, Ramanathan RK, Becerra CH, Wickham R, Armstrong D, Viele C | title = The continuum of care: a paradigm for the management of metastatic colorectal cancer | journal = The Oncologist | volume = 12 | issue = 1 | pages = 38–50 | date = January 2007 | pmid = 17227899 | doi = 10.1634/theoncologist.12-1-38 | doi-access = free }}</ref> The limitations of BSA-based dosing prevent oncologists from being able to accurately titer the dosage of 5-FU for the majority of individual patients, which results in sub-optimal treatment efficacy or excessive toxicity.<ref name="dose adjustment"/><ref name="body surface area"/>

Numerous studies have found significant relationships between concentrations of 5-FU in blood plasma and both desirable or undesirable effects on patients.<ref>{{cite journal | vauthors = Ploylearmsaeng SA, Fuhr U, Jetter A | title = How may anticancer chemotherapy with fluorouracil be individualised? | journal = Clinical Pharmacokinetics | volume = 45 | issue = 6 | pages = 567–592 | year = 2006 | pmid = 16719540 | doi = 10.2165/00003088-200645060-00002 }}</ref><ref>{{cite journal | vauthors = van Kuilenburg AB, Maring JG | title = Evaluation of 5-fluorouracil pharmacokinetic models and therapeutic drug monitoring in cancer patients | journal = Pharmacogenomics | volume = 14 | issue = 7 | pages = 799–811 | date = May 2013 | pmid = 23651027 | doi = 10.2217/pgs.13.54 }}</ref> Studies have also shown that dosing based on the concentration of 5-FU in plasma can greatly increase desirable outcomes while minimizing negative side effects of 5-FU therapy.<ref name="dose adjustment"/><ref name="individual fluorouracil">{{cite journal |vauthors=Gamelin E, Delva R, Jacob J, Merrouche Y, Raoul JL, Pezet D, Dorval E, Piot G, Morel A, Boisdron-Celle M |date=May 2008 |title=Individual fluorouracil dose adjustment based on pharmacokinetic follow-up compared with conventional dosage: results of a multicenter randomized trial of patients with metastatic colorectal cancer |journal=Journal of Clinical Oncology |publisher=ASCO Publications |publication-date=2008-05-01 |volume=26 |issue=13 |pages=2099–2105 |doi=10.1200/jco.2007.13.3934 |pmid=18445839 }}</ref> One such test that has been shown to successfully monitor 5-FU plasma levels and which "may contribute to improved efficacy and safety of commonly used 5-FU-based chemotherapies" is the My5-FU test.<ref name="multicenter evaluation"/><ref>{{cite web|url=http://Mycaretests.com|title=Customizing Chemotherapy for Better Cancer Care|publisher=MyCare Diagnostics|archive-url=https://web.archive.org/web/20140428135326/http://www.mycaretests.com/|archive-date=28 April 2014}}</ref><ref>{{cite web|url=http://bettercancercare.com|title=A Brief History of BSA Dosing|publisher=MyCare Diagnostics|url-status=live|archive-url=https://web.archive.org/web/20140428195606/http://bettercancercare.com/|archive-date=28 April 2014}}</ref>

Uridine Triacetate is a potential antidote for cases of suspected overdose.<ref>{{cite journal | vauthors = Ma WW, Saif WM, Cartwright TH, Fakih M, El-Rayes BF, King T, Vanas J, von Borstel R, Bamat MK, Posey J | title=Uridine triacetate as a lifesaving antidote for overdoses and severe early-onset 5-fluorouracil and capecitabine toxicities | journal=Journal of Clinical Oncology | volume=34 | issue=15_suppl | date=20 May 2016 | doi=10.1200/JCO.2016.34.15_suppl.e21689 | article-number=e21689}}</ref>

==Dangers to pets== The US Food and Drug Administration has highlighted the dangers of inadvertent administration to pets.<ref>{{Cite web | work = Office of the Commissioner |date=9 August 2024 |title=Fluorouracil and Pet Safety |url=https://www.fda.gov/consumers/consumer-updates/fluorouracil-and-pet-safety | publisher = U.S. Food and Drug Administration (FDA) |language=en}}</ref> While fluorouracil is sometimes used off label to treat horses, its administration to dogs in particular can be fatal.

The FDA reports that it has received 20 reports of fatal outcomes in dogs following accidental ingestion of topical fluorouracil.<ref>{{Cite web | work = Center for Veterinary Medicine |date=22 November 2024 |title=Don't Expose Pets to Prescription Topical Fluorouracil Medicine for People |url=https://www.fda.gov/animal-veterinary/animal-health-literacy/dont-expose-pets-prescription-topical-fluorouracil-medicine-people | publisher = U.S. Food and Drug Administration (FDA) |language=en}}</ref>

== Interactions ==

It may increase the INR and prothrombin times in people on warfarin.<ref name = EMC/> Fluorouracil's efficacy is decreased when used alongside allopurinol, which can be used to decrease fluorouracil induced stomatitis through use of allopurinol mouthwash.<ref name="pmid8192112">{{cite journal | vauthors = Porta C, Moroni M, Nastasi G | title = Allopurinol mouthwashes in the treatment of 5-fluorouracil-induced stomatitis | journal = American Journal of Clinical Oncology | volume = 17 | issue = 3 | pages = 246–247 | date = June 1994 | pmid = 8192112 | doi = 10.1097/00000421-199406000-00014 }}</ref>

==Pharmacology==

===Pharmacogenetics===

The dihydropyrimidine dehydrogenase (DPD) enzyme is responsible for the detoxifying metabolism of fluoropyrimidines, a class of drugs that includes 5-fluorouracil, capecitabine, and tegafur.<ref name="pmid23988873">{{cite journal | vauthors = Caudle KE, Thorn CF, Klein TE, Swen JJ, McLeod HL, Diasio RB, Schwab M | title = Clinical Pharmacogenetics Implementation Consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing | journal = Clinical Pharmacology and Therapeutics | volume = 94 | issue = 6 | pages = 640–645 | date = December 2013 | pmid = 23988873 | pmc = 3831181 | doi = 10.1038/clpt.2013.172 }}</ref> Genetic variations within the DPD gene (''DPYD'') can lead to reduced or absent DPD activity, and individuals who are heterozygous or homozygous for these variations may have partial or complete DPD deficiency; an estimated 0.2% of individuals have complete DPD deficiency.<ref name="pmid23988873"/><ref name="pmid21919607">{{cite journal | vauthors = Amstutz U, Froehlich TK, Largiadèr CR | title = Dihydropyrimidine dehydrogenase gene as a major predictor of severe 5-fluorouracil toxicity | journal = Pharmacogenomics | volume = 12 | issue = 9 | pages = 1321–1336 | date = September 2011 | pmid = 21919607 | doi = 10.2217/pgs.11.72 }}</ref> Those with partial or complete DPD deficiency have a significantly increased risk of severe or even fatal drug toxicities when treated with fluoropyrimidines; examples of toxicities include myelosuppression, neurotoxicity and hand-foot syndrome.<ref name="pmid23988873"/><ref name="pmid21919607"/>

===Mechanism of action=== 5-FU acts in several ways and is classically described as a thymidylate synthase (TS) inhibitor. Interrupting the action of this enzyme blocks synthesis of the pyrimidine thymidylate (dTMP), which is a nucleotide required for DNA replication. Thymidylate synthase methylates deoxyuridine monophosphate (dUMP) to form thymidine monophosphate (dTMP). Administration of 5-FU causes a scarcity in dTMP, so rapidly dividing cancerous cells undergo cell death via thymineless death.<ref>{{cite journal | vauthors = Longley DB, Harkin DP, Johnston PG | title = 5-fluorouracil: mechanisms of action and clinical strategies | journal = Nature Reviews. Cancer | volume = 3 | issue = 5 | pages = 330–338 | date = May 2003 | pmid = 12724731 | doi = 10.1038/nrc1074 }}</ref> Calcium folinate provides an exogenous source of reduced folinates and hence stabilises the 5-FU-TS complex, hence enhancing 5-FU's cytotoxicity.<ref>{{cite journal | vauthors = Álvarez P, Marchal JA, Boulaiz H, Carrillo E, Vélez C, Rodríguez-Serrano F, Melguizo C, Prados J, Madeddu R, Aranega A | title = 5-Fluorouracil derivatives: a patent review | journal = Expert Opinion on Therapeutic Patents | volume = 22 | issue = 2 | pages = 107–123 | date = February 2012 | pmid = 22329541 | doi = 10.1517/13543776.2012.661413 }}</ref>

5-FU is also converted inside cells into 5-fluorouridine triphosphate (5FUTP), which can be incorporated into RNA (especially ribosomal RNA, tRNA, snRNA, and mRNA) in place of uridine.<ref name=":1">{{cite journal | vauthors = Chalabi-Dchar M, Fenouil T, Machon C, Vincent A, Catez F, Marcel V, Mertani HC, Saurin JC, Bouvet P, Guitton J, Venezia ND, Diaz JJ | title = A novel view on an old drug, 5-fluorouracil: an unexpected RNA modifier with intriguing impact on cancer cell fate | journal = NAR Cancer | volume = 3 | issue = 3 | article-number = zcab032 | date = September 2021 | pmid = 34409299 | doi = 10.1093/narcan/zcab032 | pmc = 8364333 }}</ref> 5-FU incorporation into precursor rRNA impairs rRNA processing and maturation.<ref>{{cite journal | vauthors = Fang F, Hoskins J, Butler JS | title = 5-fluorouracil enhances exosome-dependent accumulation of polyadenylated rRNAs | journal = Molecular and Cellular Biology | volume = 24 | issue = 24 | pages = 10766–10776 | date = December 2004 | pmid = 15572680 | doi = 10.1128/MCB.24.24.10766-10776.2004 | pmc = 533989 }}</ref> Incorporation into small nuclear RNA (snRNA), particularly U2 snRNA, inhibits pseudouridylation, and results in faulty pre-mRNA splicing.<ref name=":1" />

==History== In 1954, Abraham Cantarow and Karl Paschkis found liver tumors absorbed radioactive uracil more readily than did normal liver cells. Charles Heidelberger, who had earlier found that fluorine in fluoroacetic acid inhibited a vital enzyme, asked Robert Duschinsky and Robert Schnitzer at Hoffmann-La Roche to synthesize fluorouracil.<ref>{{cite book | vauthors = Sneader W | title = Drug discovery: a history. | publisher = John Wiley & Sons | date = June 2005 | page = 255 }}</ref> Some credit Heidelberger and Duschinsky with the discovery that 5-fluorouracil markedly inhibited tumors in mice.<ref>{{cite journal | vauthors = Cohen S |title=50 years ago in cell biology: A virologist recalls his work on cell growth inhibition |journal=The Scientist |date=30 January 2008 |url=http://www.the-scientist.com/news/display/54259/ |url-status=live |archive-url=https://web.archive.org/web/20100919181108/http://www.the-scientist.com/news/display/54259/ |archive-date=19 September 2010 }}</ref> The original 1957 report<ref>{{cite journal | vauthors = Chu E |title=Ode to 5-Fluorouracil |journal=Clinical Colorectal Cancer |volume=6 |issue=9 |page=609 |date=September 2007 |doi=10.3816/CCC.2007.n.029 }}</ref><ref>{{cite journal | vauthors = Heidelberger C, Chaudhuri NK, Danneberg P, Mooren D, Griesbach L, Duschinsky R, Schnitzer RJ, Pleven E, Scheiner J | title = Fluorinated pyrimidines, a new class of tumour-inhibitory compounds | journal = Nature | volume = 179 | issue = 4561 | pages = 663–666 | date = March 1957 | pmid = 13418758 | doi = 10.1038/179663a0 | bibcode = 1957Natur.179..663H }}</ref> In 1958, Anthony R. Curreri, Fred J. Ansfield, Forde A. McIver, Harry A. Waisman, and Charles Heidelberger reported the first clinical findings of 5-FU's activity in cancer in humans.<ref>{{cite journal | vauthors = Jordan VC | title = A Retrospective: On Clinical Studies with 5-Fluorouracil | journal = Cancer Research | volume = 76 | issue = 4 | pages = 767–768 | date = February 2016 | pmid = 26880809 | doi = 10.1158/0008-5472.CAN-16-0150 | publisher = American Association for Cancer Research | doi-access = free }}</ref>

==Natural Occurrence== In 2003, scientists isolated 5-fluorouracil and 4 closely related compounds from the marine sponge, ''Phakellia fusca'', collected near Woody Island of the Paracel Islands in the South China Sea. <ref>{{cite journal | vauthors = Xu XH, Yao GM, Li YM, Lu JH, Lin CJ, Wang X, Kong CH | title = 5-Fluorouracil derivatives from the sponge Phakellia fusca | journal = Journal of Natural Products | volume = 66 | issue = 2 | pages = 285–288 | date = February 2003 | pmid = 12608868 | doi = 10.1021/np020034f | bibcode = 2003JNAtP..66..285X }}</ref> Fluorine-containing natural products are extremely rare with few examples such as monofluoroacetate.

==Interactive pathway map== {{FluoropyrimidineActivity WP1601}}

==Names== The name "fluorouracil" is the INN, USAN, USP name, and BAN. The form "5-fluorouracil" is often used; it shows that there is a fluorine atom on the 5th carbon of a uracil ring.

== References == {{reflist}}

== Further reading == {{refbegin}} * {{cite book | title=Medical Genetics Summaries | chapter=Fluorouracil Therapy and DPYD Genotype | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK395610/ | 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=2016 | pmid=28520376 | id=Bookshelf ID: NBK395610 | vauthors=Dean L | url=https://www.ncbi.nlm.nih.gov/books/NBK61999/ }} * {{cite journal | vauthors = Latchman J, Guastella A, Tofthagen C | title = 5-Fluorouracil toxicity and dihydropyrimidine dehydrogenase enzyme: implications for practice | journal = Clinical Journal of Oncology Nursing | volume = 18 | issue = 5 | pages = 581–585 | date = October 2014 | pmid = 25253112 | pmc = 5469441 | doi = 10.1188/14.CJON.581-585 }} {{refend}}

== External links == * {{cite web | title=Fluorouracil Topical | website=MedlinePlus | url=https://medlineplus.gov/druginfo/meds/a605010.html }}

Category:Fluoropyrimidines Category:Nucleobases Category:Organofluorides Category:Pyrimidine antagonists Category:Thymidylate synthase inhibitors Category:Uracil derivatives Category:World Health Organization essential medicines Category:Wikipedia medicine articles ready to translate