tipiracil
{{short description|Chemical compound}}
{{Infobox drug
| drug_name =
| IUPAC_name = 5-Chloro-6-[(2-imino-1-pyrrolidinyl)methyl]-2,4(1H,3H)-pyrimidinedione
| image = Tipiracil.svg
| alt =
| caption =
| tradename =
| Drugs.com =
| MedlinePlus =
| pregnancy_AU =
| pregnancy_US =
| pregnancy_category=
| licence_EU = yes
| legal_AU =
| legal_CA =
| legal_UK =
| legal_US =
| legal_status =
| routes_of_administration =
| bioavailability = ≥27%
| protein_bound = <8%
| metabolism = 10
| onset =
| elimination_half-life = 2.1–2.4 hrs
| excretion = Faeces (50%), urine (27%)
| CAS_number = 183204-74-2
| CAS_supplemental =
{{CAS|183204-72-0}} (HCl)
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = NGO10K751P
| ChemSpiderID = 13243748
| ChEMBL = 235668
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 90879
| ATCvet =
| ATC_prefix =
| ATC_suffix =
| PubChem = 6323266
| DrugBank = DB09343
| KEGG = D10467
| chemical_formula =
| C=9 | H=11 | Cl=1 | N=4 | O=2
| SMILES = C1CC(=N)N(C1)Cc2c(c(=O)[nH]c(=O)[nH]2)Cl
| StdInChI = 1S/C9H11ClN4O2/c10-7-5(12-9(16)13-8(7)15)4-14-3-1-2-6(14)11/h11H,1-4H2,(H2,12,13,15,16)
| StdInChIKey = QQHMKNYGKVVGCZ-UHFFFAOYSA-N
| solubility = 5
}}
Tipiracil is a drug used in the treatment of cancer. It is approved for use in form of the combination drug trifluridine/tipiracil for the treatment of unresectable advanced or recurrent colorectal cancer.{{cite press release | url = http://www.prnewswire.com/news-releases/taihos-lonsurfr-trifluridine-and-tipiracil-hydrochloride-tablets-approved-in-japan-for-treatment-of-advanced-metastatic-colorectal-cancer-251846651.html | title = Taiho's Lonsurf(R) (trifluridine and tipiracil hydrochloride) Tablets Approved In Japan for Treatment of Advanced Metastatic Colorectal Cancer | date = March 24, 2014}}
Tipiracil helps maintain the blood concentration of trifluridine by inhibiting the enzyme thymidine phosphorylase which metabolizes trifluridine.{{cite journal | vauthors = Tanaka N, Sakamoto K, Okabe H, Fujioka A, Yamamura K, Nakagawa F, Nagase H, Yokogawa T, Oguchi K, Ishida K, Osada A, Kazuno H, Yamada Y, Matsuo K | display-authors = 6 | title = Repeated oral dosing of TAS-102 confers high trifluridine incorporation into DNA and sustained antitumor activity in mouse models | journal = Oncology Reports | volume = 32 | issue = 6 | pages = 2319–2326 | date = December 2014 | pmid = 25230742 | pmc = 4240496 | doi = 10.3892/or.2014.3487 }}
Adverse effects
Adverse effects were not assessed independently of trifluridine, but only in the combination drug.{{citation needed|date=October 2022}}
Interactions
Only in vitro interaction studies are available. In these, tipiracil was transported by the solute carrier proteins SLC22A2 and SLC47A1. Drugs that interact with these transporters could influence blood plasma concentrations of tipiracil.{{cite book|title=Austria-Codex| veditors = Haberfeld H |publisher=Österreichischer Apothekerverlag|location=Vienna|year=2015|language=German}}
Pharmacology
=Mechanism of action=
=Pharmacokinetics=
At least 27% of tipiracil is absorbed from the gut. In cancer patients, highest blood plasma concentrations are reached after three hours. The substance has no tendency to accumulate in the body. The in vitro protein binding in human plasma is below 8%. Tipiracil is not metabolized by cytochrome P450 (CYP) enzymes. To a small extent, it is hydrolyzed to 6-hydroxymethyluracil,{{dubious|date=September 2016}} but the main fraction is excreted in unchanged form in the faeces (50%) and urine (27%). Elimination half-life is 2.1 hours on the first day and then slightly increases to 2.4 hours on the twelfth day.{{cite web |url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003897/WC500206246.pdf|title=Lonsurf: EPAR – Product Information|publisher=European Medicines Agency|date=12 May 2016}}
Tipiracil causes Cmax (highest blood plasma concentrations) of trifluridine to increase 22-fold, and its area under the curve 37-fold.
Chemistry
Tipiracil is used in form of the hydrochloride, which is a white crystalline powder. Solubility in water is 5 mg/mL;{{cite web|url=http://www.sigmaaldrich.com/catalog/product/Sigma/SML1552|title=Tipiracil hydrochloride|publisher=Sigma Aldrich|access-date=28 September 2016}} it is also soluble in 0.01 M hydrochloric acid and 0.01 M sodium hydroxide; slightly soluble in methanol; very slightly soluble in ethanol; and practically insoluble in acetonitrile, isopropyl alcohol, acetone, diisopropyl ether, and diethyl ether.{{cite web | url = https://www.drugs.com/pro/lonsurf.html | title = Lonsurf Prescribing Information | work = Drugs.com }}
COVID-19
Tipiracil has been shown to inhibit SARS-CoV-2 Nsp15 and interacts with the uridine binding pocket of the enzyme's active site using a combination of crystallography, biochemical and whole cell assays.{{cite journal | vauthors = Kim Y, Wower J, Maltseva N, Chang C, Jedrzejczak R, Wilamowski M, Kang S, Nicolaescu V, Randall G, Michalska K, Joachimiak A | display-authors = 6 | title = Tipiracil binds to uridine site and inhibits Nsp15 endoribonuclease NendoU from SARS-CoV-2 | journal = Communications Biology | volume = 4 | issue = 1 | pages = 193 | date = February 2021 | pmid = 33564093 | pmc = 7873276 | doi = 10.1038/s42003-021-01735-9 }}
It had previously been suggested in a computational drug repurposing study as the most promising hit targeting the main SARS-CoV-2 protease.{{cite journal | vauthors = Baby K, Maity S, Mehta CH, Suresh A, Nayak UY, Nayak Y | title = Targeting SARS-CoV-2 Main Protease: A Computational Drug Repurposing Study | journal = Archives of Medical Research | volume = 52 | issue = 1 | pages = 38–47 | date = January 2021 | pmid = 32962867 | pmc = 7498210 | doi = 10.1016/j.arcmed.2020.09.013 }}