Tipiracil

Identification

Name

Tipiracil

Accession Number

DB09343

Description

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

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Tipiracil (DB09343)

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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

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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

Associated Conditions

• Metastatic Colorectal Cancer (MCRC)

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

Target	Actions	Organism
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

Hover over products below to view reaction partners

• Tipiracil
  • 6-(hydroxymethyl)uracil

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

Affected organisms

• Humans and other mammals

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Amantadine	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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Food Interactions

• Take with food.

Products

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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 (6.14 mg) + Trifluridine (15 mg)	Tablet	Oral	Taiho Pharma Canada, Inc.	2018-03-22	Not applicable
Lonsurf	Tipiracil hydrochloride (8.19 mg) + Trifluridine (20 mg)	Tablet, film coated	Oral	Les Laboratoires Servier	2016-09-08	Not applicable
Lonsurf	Tipiracil hydrochloride (6.14 mg) + Trifluridine (15 mg)	Tablet, film coated	Oral	Les Laboratoires Servier	2016-09-08	Not applicable
Lonsurf	Tipiracil hydrochloride (8.19 mg) + Trifluridine (20 mg)	Tablet, film coated	Oral	Les Laboratoires Servier	2016-09-08	Not applicable
Lonsurf	Tipiracil hydrochloride (6.14 mg) + Trifluridine (15 mg)	Tablet, film coated	Oral	Les Laboratoires Servier	2016-09-08	Not applicable
Lonsurf	Tipiracil hydrochloride (8.19 mg/1) + Trifluridine (20 mg/1)	Tablet, film coated	Oral	Taiho Pharmaceutical Co., Ltd.	2015-09-22	Not applicable
Lonsurf	Tipiracil (8.19 mg) + Trifluridine (20 mg)	Tablet	Oral	Taiho Pharma Canada, Inc.	2018-03-22	Not applicable
Lonsurf	Tipiracil hydrochloride (8.19 mg) + Trifluridine (20 mg)	Tablet, film coated	Oral	Les Laboratoires Servier	2016-09-08	Not applicable
Lonsurf	Tipiracil hydrochloride (6.14 mg) + Trifluridine (15 mg)	Tablet, film coated	Oral	Les Laboratoires Servier	2016-09-08	Not applicable
Lonsurf	Tipiracil hydrochloride (6.14 mg/1) + Trifluridine (15 mg/1)	Tablet, film coated	Oral	Taiho Pharmaceutical Co., Ltd.	2015-09-22	Not applicable

Categories

Drug Categories

• MATE 1 Substrates
• MATE 1 Substrates with a Narrow Therapeutic Index
• MATE substrates
• Narrow Therapeutic Index Drugs
• OCT2 Substrates
• OCT2 Substrates with a Narrow Therapeutic Index
• Pyrimidines
• Pyrimidinones
• Thymidine Phosphorylase Inhibitor

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 / Carboxamidines / Azacyclic compounds / Organochlorides / Organooxygen compounds / Hydrocarbon derivatives / Organopnictogen compounds / Organic oxides

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Substituents

Amidine / Aromatic heteromonocyclic compound / Aryl chloride / Aryl halide / Azacycle / Carboximidamide / Carboxylic acid amidine / Halopyrimidine / Heteroaromatic compound / Hydrocarbon derivative / Hydropyrimidine / Imidolactam / Lactam / N-alkylpyrrolidine / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organochloride / Organohalogen compound / Organonitrogen compound / Organooxygen compound / Organopnictogen compound / Pyrimidone / Pyrrolidine / Urea / Vinylogous amide

show 16 more

Molecular Framework

Aromatic heteromonocyclic compounds

External Descriptors

Not Available

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. [PubMed:27162472]
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. [PubMed:26428513]
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. [PubMed:29056855]
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. [PubMed:12639965]
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. [PubMed:23182191]
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. [PubMed:28111727]
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. [PubMed:26918279]
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. [PubMed:26787503]
9. EMA.europa [Link]
10. EMA.europa [Link]
11. Australia TGA: Trifluridine/Tipiracil Clinical Evaluation Report [Link]

External Links

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

Phase	Status	Purpose	Conditions	Count
3	Active Not Recruiting	Treatment	Metastatic Colorectal Cancer (MCRC)	1
3	Completed	Treatment	Metastatic Colorectal Cancer (MCRC)	1
3	Not Yet Recruiting	Treatment	Neoplasms, Colorectal	1
3	Recruiting	Treatment	Circulating Tumor DNA / Neoplasms, Colorectal / Trifluridine and Tipiracil	1
3	Recruiting	Treatment	Refractory, metastatic Colorectal cancer	1
3	Withdrawn	Treatment	Carcinoma NOS / Metastatic Colorectal Cancer (MCRC)	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 Cancers	1
2	Active Not Recruiting	Treatment	Squamous Cell Lung Carcinoma	1
2	Completed	Treatment	Metastatic Colorectal Cancer (MCRC)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet	Oral
Tablet, film coated	Oral

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US7799783	No	2010-09-21	2026-12-16
US5744475	No	1998-04-28	2016-03-28
US6479500	No	2002-11-12	2020-03-16
US9527833	No	2016-12-27	2034-06-17
USRE46284	No	2017-01-24	2026-12-16
US10456399	No	2019-10-29	2037-02-03
US10457666	No	2019-10-29	2034-06-17

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

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Details1. Thymidine phosphorylase

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

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Drug created on November 27, 2015 20:26 / Updated on February 21, 2021 18:52