Tipiracil
Identification
- Summary
Tipiracil is a thymidine phosphorylase inhibitor used as an adjunct treatment of adult patients with certain types of gastric or colorectal malignancies.
- Brand Names
- Lonsurf
- Generic Name
- Tipiracil
- DrugBank Accession Number
- DB09343
- Background
Tipiracil is a thymidine phosphorylase inhibitor. It is used in combination with trifluridine, in a ratio of 1:0.5, to form TAS-102. The main function of Tipiracil in TAS-102 is to increase trifluridine bioavailability by inhibiting its catabolism.2 TAS-102 is indicated for the treatment of metastatic colorectal cancer which has been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, or with an anti-VEGF or anti-EGFR therapy.1
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Tipiracil (DB09343)
- Weight
- Average: 242.662
Monoisotopic: 242.057053323 - Chemical Formula
- C9H11ClN4O2
- Synonyms
- 5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidinedione
- 5-chloro-6-[(2-iminopyrrolidin-1-yl)methyl]-1H-pyrimidine-2,4-dione
- Tipiracil
- Tipiracilo
Pharmacology
- Indication
Tipiracil, in combination with trifluridine, is indicated for the treatment of refractory mestastatic colorectal cancer patients who keep progressing despite of treatment with standard chemotherapy and biologics.3
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- Contraindications & Blackbox Warnings
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Tipiracil prevents trifluridine conversion into 5-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, which is an inactive major metabolite, by inhibiting the enzyme thymidine phosphorylase. Thus, tipiracil is able to increase trifluridine bioavailability. On the other hand, thymidine phsophorylase is a known platelet-derived endothelial cell growth factor and its inhibition generates an indirect antiangiogenic benefit.3
- Mechanism of action
Tipiracil is a thymidine phosphorylase inhibitor. Its function prevents the breakdownof the active component of trifluridine, thus increasing the bioavailability of trifluridine and boosting its systemic presence.1 In addition, it is reported that thymidine phosphorylase is an angiogenic factor usually overexpressed in solid tumors.4 There is a direct association of thymidine phosphorylase with a poor prognosis; where the tumors with an elevated expression of this enzyme tend to present an increased angiogenesis and ergo, be more malignant. Therefore, it has been suggested that tipiracil presents an aditional function by downregulating tumoral angiogenesis.5
Target Actions Organism AThymidine phosphorylase inhibitorHumans - Absorption
Absorption of tipiracil is suggested to be done by the gastrointestinal tract. 8 Administration of a single 35 mg/m2 dose of TAS-102 containing tipiracil and trifluridine, generates the absoprtion rates of tipiracil of AUC 301 ng h/ml, maximum observed plasma concentration (Cmax) 69 ng/ml and time for maximum observed plasma concentration (Tmax) 3 h. 6 The consumption of a high-fat and high-calorie meal can decrease Cmax and AUC by 40%.7
- Volume of distribution
After a single TAS-102 dose if 35 mg/m2 in patients with advanced solid tumors, it was recorded a volume of distribution of tipiracil of 333 L.9
- Protein binding
Tipiracil does not bind highly to proteins and presents a plasma protein binding below 8%.10
- Metabolism
Tipiracil does not undergo much metabolism upon first pass. It is not metabolized by the liver or hepatocytes, nor by the cytochrome P450 enzymes. The only tipiracil-derived metabolite found in very small quantities in human plasma, urine or faeces is 6-hydroxymethyluracil (6-HMU) which is not unique of tipiracil. This metabolite is though to be formed either by enterobacterial metabolism. In plasma, this two metabolites can be found in a proportion of tipiracil 53.1% and 6-HMU 30.9%.8
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- Route of elimination
The main fraction of tipiracil is excreted unchanged in the mainly in the faeces (49.7%) followed by the urine (27%). From the urine excretion 79.1% is accounted by unchanged tipiracil while 14% is 6-HMU. On the other hand, the faeces elimination analysis was formed by 48.2% unchanged tipiracil and 34.4% 6-HMU.8
- Half-life
Tipiracil mean elmination half-life is 2.1 hours.6
- Clearance
A single 35mg/m2 of TAS-102 in patients with advanced solid tumors produces a clearance rate of tipiracil of 109 L/hr, with a recovery rate of 77% of the total dose.9
- Adverse Effects
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates.Improve decision support & research outcomes with our structured adverse effects data.- Toxicity
TAS-102 is a cytotoxic drug, therefore this combination drug can cause myelosupression, including neutropenia, anemia, thrombocytopenia, and febrile neutropenia. According to pre-clinical studies, TAS-102 presents also embryo-fetal toxicity.1
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAmantadine The excretion of Tipiracil can be decreased when combined with Amantadine. Amiloride The excretion of Tipiracil can be decreased when combined with Amiloride. Aminohippuric acid The excretion of Tipiracil can be decreased when combined with Aminohippuric acid. Amiodarone The excretion of Tipiracil can be decreased when combined with Amiodarone. Apalutamide The excretion of Tipiracil can be decreased when combined with Apalutamide. Baricitinib The excretion of Tipiracil can be decreased when combined with Baricitinib. Bupropion The excretion of Tipiracil can be decreased when combined with Bupropion. Chlorpheniramine The excretion of Tipiracil can be decreased when combined with Chlorpheniramine. Choline The excretion of Tipiracil can be decreased when combined with Choline. Choline salicylate The excretion of Tipiracil can be decreased when combined with Choline salicylate. 
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- Take with food.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Tipiracil hydrochloride 4H59KLQ0A4 183204-72-0 KGHYQYACJRXCAT-UHFFFAOYSA-N - Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Lonsurf Tipiracil hydrochloride (8.19 mg) + Trifluridine (20 mg) Tablet, film coated Oral Les Laboratoires Servier 2016-09-08 Not applicable EU 
Lonsurf Tipiracil hydrochloride (6.14 mg/1) + Trifluridine (15 mg/1) Tablet, film coated Oral Taiho Pharmaceutical Co., Ltd. 2015-09-22 Not applicable US 
Lonsurf Tipiracil hydrochloride (6.14 mg) + Trifluridine (15 mg) Tablet, film coated Oral Les Laboratoires Servier 2016-09-08 Not applicable EU Lonsurf Tipiracil (6.14 mg) + Trifluridine (15 mg) Tablet Oral Taiho Pharma Canada, Inc. 2018-03-22 Not applicable Canada 
Lonsurf Tipiracil hydrochloride (6.14 mg) + Trifluridine (15 mg) Tablet, film coated Oral Les Laboratoires Servier 2016-09-08 Not applicable EU Lonsurf Tipiracil hydrochloride (8.19 mg) + Trifluridine (20 mg) Tablet, film coated Oral Les Laboratoires Servier 2016-09-08 Not applicable EU Lonsurf Tipiracil hydrochloride (8.19 mg/1) + Trifluridine (20 mg/1) Tablet, film coated Oral Taiho Pharmaceutical Co., Ltd. 2015-09-22 Not applicable US Lonsurf Tipiracil hydrochloride (8.19 mg) + Trifluridine (20 mg) Tablet, film coated Oral Les Laboratoires Servier 2016-09-08 Not applicable EU Lonsurf Tipiracil (8.19 mg) + Trifluridine (20 mg) Tablet Oral Taiho Pharma Canada, Inc. 2018-03-22 Not applicable Canada Lonsurf Tipiracil hydrochloride (6.14 mg) + Trifluridine (15 mg) Tablet, film coated Oral Les Laboratoires Servier 2016-09-08 Not applicable EU
Categories
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as halopyrimidines. These are aromatic compounds containing a halogen atom linked to a pyrimidine ring. Pyrimidine is a 6-membered ring consisting of four carbon atoms and two nitrogen centers at the 1- and 3- ring positions.
- Kingdom
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Class
- Diazines
- Sub Class
- Pyrimidines and pyrimidine derivatives
- Direct Parent
- Halopyrimidines
- Alternative Parents
- Pyrimidones / Aryl chlorides / Hydropyrimidines / Imidolactams / N-alkylpyrrolidines / Vinylogous amides / Heteroaromatic compounds / Ureas / Lactams / Carboximidamides show 7 more
- Substituents
- Amidine / Aromatic heteromonocyclic compound / Aryl chloride / Aryl halide / Azacycle / Carboximidamide / Carboxylic acid amidine / Halopyrimidine / Heteroaromatic compound / Hydrocarbon derivative show 16 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- NGO10K751P
- CAS number
- 183204-74-2
- InChI Key
- QQHMKNYGKVVGCZ-UHFFFAOYSA-N
- InChI
- InChI=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)
- IUPAC Name
- 5-chloro-6-[(2-iminopyrrolidin-1-yl)methyl]-1,2,3,4-tetrahydropyrimidine-2,4-dione
- SMILES
- ClC1=C(CN2CCCC2=N)NC(=O)NC1=O
References
- General References
- Kish T, Uppal P: Trifluridine/Tipiracil (Lonsurf) for the Treatment of Metastatic Colorectal Cancer. P T. 2016 May;41(5):314-25. [Article]
- Lenz HJ, Stintzing S, Loupakis F: TAS-102, a novel antitumor agent: a review of the mechanism of action. Cancer Treat Rev. 2015 Nov;41(9):777-83. doi: 10.1016/j.ctrv.2015.06.001. Epub 2015 Jun 6. [Article]
- Puthiamadathil JM, Weinberg BA: Emerging combination therapies for metastatic colorectal cancer - impact of trifluridine/tipiracil. Cancer Manag Res. 2017 Oct 3;9:461-469. doi: 10.2147/CMAR.S113320. eCollection 2017. [Article]
- Hotchkiss KA, Ashton AW, Schwartz EL: Thymidine phosphorylase and 2-deoxyribose stimulate human endothelial cell migration by specific activation of the integrins alpha 5 beta 1 and alpha V beta 3. J Biol Chem. 2003 May 23;278(21):19272-9. Epub 2003 Mar 13. [Article]
- Peters GJ, Bijnsdorp IV: TAS-102: more than an antimetabolite. Lancet Oncol. 2012 Dec;13(12):e518-9. doi: 10.1016/S1470-2045(12)70426-6. [Article]
- Cleary JM, Rosen LS, Yoshida K, Rasco D, Shapiro GI, Sun W: A phase 1 study of the pharmacokinetics of nucleoside analog trifluridine and thymidine phosphorylase inhibitor tipiracil (components of TAS-102) vs trifluridine alone. Invest New Drugs. 2017 Apr;35(2):189-197. doi: 10.1007/s10637-016-0409-9. Epub 2017 Jan 23. [Article]
- Yoshino T, Kojima T, Bando H, Yamazaki T, Naito Y, Mukai H, Fuse N, Goto K, Ito Y, Doi T, Ohtsu A: Effect of food on the pharmacokinetics of TAS-102 and its efficacy and safety in patients with advanced solid tumors. Cancer Sci. 2016 May;107(5):659-65. doi: 10.1111/cas.12912. Epub 2016 Mar 28. [Article]
- Lee JJ, Seraj J, Yoshida K, Mizuguchi H, Strychor S, Fiejdasz J, Faulkner T, Parise RA, Fawcett P, Pollice L, Mason S, Hague J, Croft M, Nugteren J, Tedder C, Sun W, Chu E, Beumer JH: Human mass balance study of TAS-102 using (14)C analyzed by accelerator mass spectrometry. Cancer Chemother Pharmacol. 2016 Mar;77(3):515-26. doi: 10.1007/s00280-016-2965-2. Epub 2016 Jan 19. [Article]
- EMA.europa [Link]
- EMA.europa [Link]
- Australia TGA: Trifluridine/Tipiracil Clinical Evaluation Report [Link]
- External Links
- PubChem Compound
- 6323266
- PubChem Substance
- 310265218
- ChemSpider
- 13243748
- BindingDB
- 20079
- 1670304
- ChEBI
- 90879
- ChEMBL
- CHEMBL235668
- ZINC
- ZINC000100032379
- Wikipedia
- Tipiracil
- FDA label
- Download (490 KB)
- MSDS
- Download (30 KB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Active Not Recruiting Treatment Metastatic Colorectal Cancer (CRC) 1 3 Completed Treatment Metastatic Colorectal Cancer (CRC) 1 3 Not Yet Recruiting Treatment Colorectal Carcinoma (CRC) 1 3 Recruiting Treatment Circulating Tumor DNA / Neoplasms, Colorectal / Trifluridine and Tipiracil 1 3 Recruiting Treatment Gastroesophageal Cancer (GC) 1 3 Recruiting Treatment Neoplasms, Colorectal 1 3 Recruiting Treatment Refractory, metastatic Colorectal cancer 1 3 Withdrawn Treatment Carcinoma / Metastatic Colorectal Cancer (CRC) 1 2 Active Not Recruiting Treatment Cholangiocarcinomas / Stage III Gallbladder Cancer AJCC V7 / Stage IIIA Gallbladder Cancer AJCC v7 / Stage IIIB Gallbladder Cancer AJCC v7 / Stage IV Gallbladder Cancer AJCC v7 / Stage IVA Gallbladder Cancer AJCC v7 / Stage IVB Gallbladder Cancer AJCC v7 1 2 Active Not Recruiting Treatment Colorectal Carcinoma (CRC) 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet Oral Tablet, film coated Oral Tablet, film coated Oral 6.14 mg Tablet, film coated Oral 8.19 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US7799783 No 2010-09-21 2026-12-16 US US5744475 No 1998-04-28 2016-03-28 US US6479500 No 2002-11-12 2020-03-16 US US9527833 No 2016-12-27 2034-06-17 US USRE46284 No 2017-01-24 2026-12-16 US US10456399 No 2019-10-29 2037-02-03 US US10457666 No 2019-10-29 2034-06-17 US US10960004 No 2021-03-30 2037-02-03 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 245ºC (decomposition) Not Available water solubility 5 mg/ml (warmed) Sigma-aldrich MSDS - Predicted Properties
Property Value Source Water Solubility 0.731 mg/mL ALOGPS logP -0.21 ALOGPS logP -2 ChemAxon logS -2.5 ALOGPS pKa (Strongest Acidic) 7.28 ChemAxon pKa (Strongest Basic) 11.55 ChemAxon Physiological Charge 1 ChemAxon Hydrogen Acceptor Count 4 ChemAxon Hydrogen Donor Count 3 ChemAxon Polar Surface Area 85.29 Å2 ChemAxon Rotatable Bond Count 2 ChemAxon Refractivity 69.89 m3·mol-1 ChemAxon Polarizability 22.48 Å3 ChemAxon Number of Rings 2 ChemAxon Bioavailability 1 ChemAxon Rule of Five Yes ChemAxon Ghose Filter No ChemAxon Veber's Rule No ChemAxon MDDR-like Rule No ChemAxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted GC-MS Spectrum - GC-MS Predicted GC-MS Not Available Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Transferase activity, transferring pentosyl groups
- Specific Function
- May have a role in maintaining the integrity of the blood vessels. Has growth promoting activity on endothelial cells, angiogenic activity in vivo and chemotactic activity on endothelial cells in v...
- Gene Name
- TYMP
- Uniprot ID
- P19971
- Uniprot Name
- Thymidine phosphorylase
- Molecular Weight
- 49954.965 Da
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Quaternary ammonium group transmembrane transporter activity
- Specific Function
- Mediates tubular uptake of organic compounds from circulation. Mediates the influx of agmatine, dopamine, noradrenaline (norepinephrine), serotonin, choline, famotidine, ranitidine, histamin, creat...
- Gene Name
- SLC22A2
- Uniprot ID
- O15244
- Uniprot Name
- Solute carrier family 22 member 2
- Molecular Weight
- 62579.99 Da
References
- Martinez-Perez J, Riesco-Martinez MC, Garcia-Carbonero R: The safety of trifluridine and tipiracil for the treatment of metastatic colorectal cancer. Expert Opin Drug Saf. 2018 Jun;17(6):643-650. doi: 10.1080/14740338.2018.1475557. Epub 2018 May 23. [Article]
- Australia TGA: Trifluridine/Tipiracil Clinical Evaluation Report [Link]
- Tipiracil EMA [File]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Monovalent cation:proton antiporter activity
- Specific Function
- Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide (NMN), metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfat...
- Gene Name
- SLC47A1
- Uniprot ID
- Q96FL8
- Uniprot Name
- Multidrug and toxin extrusion protein 1
- Molecular Weight
- 61921.585 Da
References
- Martinez-Perez J, Riesco-Martinez MC, Garcia-Carbonero R: The safety of trifluridine and tipiracil for the treatment of metastatic colorectal cancer. Expert Opin Drug Saf. 2018 Jun;17(6):643-650. doi: 10.1080/14740338.2018.1475557. Epub 2018 May 23. [Article]
- Australia TGA: Trifluridine/Tipiracil Clinical Evaluation Report [Link]
- Tipiracil EMA [File]
Drug created on November 27, 2015 20:26 / Updated on May 07, 2021 21:42