Identification

Name
Tipiracil
Accession Number
DB09343
Type
Small Molecule
Groups
Approved, Investigational
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]

Structure
Thumb
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
  • TPI
Product Ingredients
IngredientUNIICASInChI Key
Tipiracil hydrochloride4H59KLQ0A4183204-72-0KGHYQYACJRXCAT-UHFFFAOYSA-N
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
LonsurfTipiracil hydrochloride (8.19 mg/1) + Trifluridine (20 mg/1)Tablet, film coatedOralTaisho Pharmaceutical Co., Ltd.2015-09-22Not applicableUs
LonsurfTipiracil (6.14 mg) + Trifluridine (15 mg)TabletOralTaiho Pharma Canada, Inc.2018-03-22Not applicableCanada
LonsurfTipiracil hydrochloride (6.14 mg/1) + Trifluridine (15 mg/1)Tablet, film coatedOralTaisho Pharmaceutical Co., Ltd.2015-09-22Not applicableUs
LonsurfTipiracil (8.19 mg) + Trifluridine (20 mg)TabletOralTaiho Pharma Canada, Inc.2018-03-22Not applicableCanada
Categories
UNII
NGO10K751P
CAS number
183204-74-2
Weight
Average: 242.662
Monoisotopic: 242.057053323
Chemical Formula
C9H11ClN4O2
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

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]

Associated Conditions
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
Human
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]

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]

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
DrugInteraction
AgmatineThe serum concentration of Tipiracil can be increased when it is combined with Agmatine.
AmantadineThe excretion of Tipiracil can be decreased when combined with Amantadine.
AmilorideThe excretion of Tipiracil can be decreased when combined with Amiloride.
ChlormadinoneThe therapeutic efficacy of Chlormadinone can be decreased when used in combination with Tipiracil.
CholineThe excretion of Tipiracil can be decreased when combined with Choline.
Choline salicylateThe serum concentration of Tipiracil can be increased when it is combined with Choline salicylate.
CimetidineThe serum concentration of Tipiracil can be increased when it is combined with Cimetidine.
CisplatinThe excretion of Tipiracil can be decreased when combined with Cisplatin.
CloprostenolThe therapeutic efficacy of Cloprostenol can be decreased when used in combination with Tipiracil.
CocaineThe excretion of Tipiracil can be decreased when combined with Cocaine.
Food Interactions
Not Available

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]
External Links
PubChem Compound
6323266
PubChem Substance
310265218
ChemSpider
13243748
BindingDB
20079
ChEBI
90879
ChEMBL
CHEMBL235668
Wikipedia
Tipiracil
FDA label
Download (490 KB)
MSDS
Download (30 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingTreatmentNeoplasms Malignant1
1CompletedTreatmentMetastatic Colorectal Cancers1
1Not Yet RecruitingTreatmentAdvanced or Metastatic Colorectal Cancer (mCRC) / Advanced or Metastatic Solid Tumors1
1RecruitingTreatmentHepatic Metastases / Malignant Neoplasm of Colon / Rectal Carcinoma1
1RecruitingTreatmentPretreated Metastatic Colorectal Cancer1
1RecruitingTreatmentRAS Family Gene Mutation / Stage III Colon Cancer AJCC v7 / Stage III Colorectal Cancer AJCC v7 / Stage III Rectal Cancer AJCC v7 / Stage IIIA Colon Cancer AJCC v7 / Stage IIIA Colorectal Cancer AJCC v7 / Stage IIIA Rectal Cancer AJCC v7 / Stage IIIB Colon Cancer AJCC v7 / Stage IIIB Colorectal Cancer AJCC v7 / Stage IIIB Rectal Cancer AJCC v7 / Stage IIIC Colon Cancer AJCC v7 / Stage IIIC Colorectal Cancer AJCC v7 / Stage IIIC Rectal Cancer AJCC v7 / Stage IV Colon Cancer AJCC v7 / Stage IV Colorectal Cancer AJCC v7 / Stage IV Rectal Cancer AJCC v7 / Stage IVA Colon Cancer AJCC v7 / Stage IVA Colorectal Cancer AJCC v7 / Stage IVA Rectal Cancer AJCC v7 / Stage IVB Colon Cancer AJCC v7 / Stage IVB Colorectal Cancer AJCC v7 / Stage IVB Rectal Cancer AJCC v71
1RecruitingTreatmentRectal Adenocarcinoma / Recurrent Rectal Carcinoma / Stage IV Rectal Cancer AJCC v7 / Stage IVA Rectal Cancer AJCC v7 / Stage IVB Rectal Cancer AJCC v71
1, 2RecruitingTreatmentAdvanced Gastric Cancer / Colorectal Adenocarcinoma / Gastric Adenocarcinoma / Non-Resectable Cholangiocarcinoma / Pancreatic Adenocarcinoma Metastatic / Stage IV Colorectal Cancer / Stage IV Pancreatic Cancer / Stage IVA Colorectal Cancer / Stage IVB Colorectal Cancer / Unresectable Pancreatic Carcinoma1
1, 2RecruitingTreatmentColorectal Cancers1
2CompletedTreatmentRefractory, metastatic Colorectal cancer1
2Not Yet RecruitingTreatmentAdenocarcinomas of the Gastroesophageal Junction / Gastric Adenocarcinoma / Malignant Neoplasm of Stomach1
2RecruitingTreatmentCholangiocarcinomas / 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 v71
2RecruitingTreatmentMalignant Neoplasm of Pancreas1
2RecruitingTreatmentPreviously Treated Metastatic Colorectal Cancer1
2RecruitingTreatmentSquamous Cell Lung Carcinoma1
2TerminatedTreatmentMetastatic Colorectal Cancers1
Not AvailableCompletedPreventionMyoma of Uterus1
Not AvailableRecruitingNot AvailableMetastatic Colorectal Cancers1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral
Tablet, film coatedOral
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7799783No2006-12-162026-12-16Us
US5744475No1996-03-282016-03-28Us
US6479500No2000-03-162020-03-16Us
US9527833No2014-06-172034-06-17Us
USRE46284No2006-12-162026-12-16Us

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

Taxonomy

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
Halopyrimidine / Pyrimidone / Aryl chloride / Aryl halide / Hydropyrimidine / N-alkylpyrrolidine / Imidolactam / Pyrrolidine / Heteroaromatic compound / Vinylogous amide
show 16 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
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

Carriers

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Carrier
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. Suenaga M, Schirripa M, Cao S, Zhang W, Yang D, Dadduzio V, Salvatore L, Borelli B, Pietrantonio F, Ning Y, Okazaki S, Berger MD, Miyamoto Y, Gopez R Jr, Barzi A, Yamaguchi T, Loupakis F, Lenz HJ: Potential role of polymorphisms in the transporter genes ENT1 and MATE1/OCT2 in predicting TAS-102 efficacy and toxicity in patients with refractory metastatic colorectal cancer. Eur J Cancer. 2017 Oct 6;86:197-206. doi: 10.1016/j.ejca.2017.08.033. [PubMed:28992563]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Carrier
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. Suenaga M, Schirripa M, Cao S, Zhang W, Yang D, Dadduzio V, Salvatore L, Borelli B, Pietrantonio F, Ning Y, Okazaki S, Berger MD, Miyamoto Y, Gopez R Jr, Barzi A, Yamaguchi T, Loupakis F, Lenz HJ: Potential role of polymorphisms in the transporter genes ENT1 and MATE1/OCT2 in predicting TAS-102 efficacy and toxicity in patients with refractory metastatic colorectal cancer. Eur J Cancer. 2017 Oct 6;86:197-206. doi: 10.1016/j.ejca.2017.08.033. [PubMed:28992563]

Drug created on November 27, 2015 13:26 / Updated on October 01, 2018 16:37