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
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 adult patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy. This combination use is also used to treat metastatic gastric or gastroesophageal junction adenocarcinoma previously treated with at least two prior lines of chemotherapy that included a fluoropyrimidine, a platinum, either a taxane or irinotecan, and if appropriate, HER2/neu-targeted therapy.12

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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

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

TargetActionsOrganism
AThymidine phosphorylase
inhibitor
Humans
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
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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.
DrugInteraction
AmantadineThe excretion of Tipiracil can be decreased when combined with Amantadine.
AmilorideThe excretion of Tipiracil can be decreased when combined with Amiloride.
Aminohippuric acidThe excretion of Tipiracil can be decreased when combined with Aminohippuric acid.
AmiodaroneThe excretion of Tipiracil can be decreased when combined with Amiodarone.
ApalutamideThe excretion of Tipiracil can be decreased when combined with Apalutamide.
BupropionThe excretion of Tipiracil can be decreased when combined with Bupropion.
ChlorpheniramineThe excretion of Tipiracil can be decreased when combined with Chlorpheniramine.
CholineThe excretion of Tipiracil can be decreased when combined with Choline.
Choline salicylateThe excretion of Tipiracil can be decreased when combined with Choline salicylate.
CimetidineThe excretion of Tipiracil can be decreased when combined with Cimetidine.
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Food Interactions
  • Take with food.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Tipiracil hydrochloride4H59KLQ0A4183204-72-0KGHYQYACJRXCAT-UHFFFAOYSA-N
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
LonsurfTipiracil hydrochloride (6.14 mg) + Trifluridine (15 mg)TabletOralTaiho Pharma Canada, Inc.2018-03-22Not applicableCanada flag
LonsurfTipiracil hydrochloride (8.19 mg) + Trifluridine (20 mg)Tablet, film coatedOralLes Laboratoires Servier2016-09-08Not applicableEU flag
LonsurfTipiracil hydrochloride (6.14 mg) + Trifluridine (15 mg)Tablet, film coatedOralLes Laboratoires Servier2016-09-08Not applicableEU flag
LonsurfTipiracil hydrochloride (8.19 mg) + Trifluridine (20 mg)Tablet, film coatedOralLes Laboratoires Servier2016-09-08Not applicableEU flag
LonsurfTipiracil hydrochloride (8.19 mg/1) + Trifluridine (20 mg/1)Tablet, film coatedOralTaiho Pharmaceutical Co., Ltd.2015-09-22Not applicableUS flag
LonsurfTipiracil hydrochloride (6.14 mg) + Trifluridine (15 mg)Tablet, film coatedOralLes Laboratoires Servier2016-09-08Not applicableEU flag
LonsurfTipiracil hydrochloride (8.19 mg) + Trifluridine (20 mg)TabletOralTaiho Pharma Canada, Inc.2018-03-22Not applicableCanada flag
LonsurfTipiracil hydrochloride (8.19 mg) + Trifluridine (20 mg)Tablet, film coatedOralLes Laboratoires Servier2016-09-08Not applicableEU flag
LonsurfTipiracil hydrochloride (6.14 mg) + Trifluridine (15 mg)Tablet, film coatedOralLes Laboratoires Servier2016-09-08Not applicableEU flag
LonsurfTipiracil hydrochloride (6.14 mg/1) + Trifluridine (15 mg/1)Tablet, film coatedOralTaiho Pharmaceutical Co., Ltd.2015-09-22Not applicableUS flag

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
  1. Kish T, Uppal P: Trifluridine/Tipiracil (Lonsurf) for the Treatment of Metastatic Colorectal Cancer. P T. 2016 May;41(5):314-25. [Article]
  2. 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]
  3. 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]
  4. 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]
  5. 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]
  6. 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]
  7. 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]
  8. 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]
  9. EMA.europa [Link]
  10. EMA.europa [Link]
  11. Australia TGA: Trifluridine/Tipiracil Clinical Evaluation Report [Link]
  12. FDA Approved Drug Products: LONSURF (trifluridine and tipiracil) tablets, for oral use [Link]
PubChem Compound
6323266
PubChem Substance
310265218
ChemSpider
13243748
BindingDB
20079
RxNav
1670304
ChEBI
90879
ChEMBL
CHEMBL235668
ZINC
ZINC000100032379
Wikipedia
Tipiracil
FDA label
Download (490 KB)
MSDS
Download (30 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentColorectal Cancer1
3Active Not RecruitingTreatmentColorectal Neoplasms1
3Active Not RecruitingTreatmentRefractory, metastatic Colorectal cancer1
3CompletedTreatmentMetastatic Colorectal Cancer (CRC)2
3RecruitingTreatmentCirculating Tumor DNA / Colorectal Neoplasms / Trifluridine and Tipiracil1
3RecruitingTreatmentColorectal Cancer2
3RecruitingTreatmentColorectal Neoplasms1
3RecruitingTreatmentGastroesophageal Cancer (GC)1
3RecruitingTreatmentMetastatic Colorectal Cancer (CRC)1
3WithdrawnTreatmentCarcinoma / Metastatic Colorectal Cancer (CRC)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral
Tablet, film coatedOral
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US7799783No2010-09-212026-12-16US flag
US5744475No1998-04-282016-03-28US flag
US6479500No2002-11-122020-03-16US flag
US9527833No2016-12-272034-06-17US flag
USRE46284No2017-01-242026-12-16US flag
US10456399No2019-10-292037-02-03US flag
US10457666No2019-10-292034-06-17US flag
US10960004No2021-03-302037-02-03US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)245ºC (decomposition)Not Available
water solubility5 mg/ml (warmed)Sigma-aldrich MSDS
Predicted Properties
PropertyValueSource
Water Solubility0.731 mg/mLALOGPS
logP-0.21ALOGPS
logP-2Chemaxon
logS-2.5ALOGPS
pKa (Strongest Acidic)7.28Chemaxon
pKa (Strongest Basic)11.55Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count4Chemaxon
Hydrogen Donor Count3Chemaxon
Polar Surface Area85.29 Å2Chemaxon
Rotatable Bond Count2Chemaxon
Refractivity69.89 m3·mol-1Chemaxon
Polarizability22.48 Å3Chemaxon
Number of Rings2Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

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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
  1. 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]
  2. Australia TGA: Trifluridine/Tipiracil Clinical Evaluation Report [Link]
  3. 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
  1. 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]
  2. Australia TGA: Trifluridine/Tipiracil Clinical Evaluation Report [Link]
  3. Tipiracil EMA [File]

Drug created at November 27, 2015 20:26 / Updated at March 24, 2022 01:23