TIPIRACIL HYDROCHLORIDE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C9H11ClN4O2.ClH
Molecular Weight	279.123
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

Cl.ClC1=C(CN2CCCC2=N)NC(=O)NC1=O

InChI

InChIKey=KGHYQYACJRXCAT-UHFFFAOYSA-N

InChI=1S/C9H11ClN4O2.ClH/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);1H

HIDE SMILES / InChI

Molecular Formula	ClH
Molecular Weight	36.461
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Molecular Formula	C9H11ClN4O2
Molecular Weight	242.662
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207981s000lbl.pdf
Curator's Comment: The description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/28979148 | https://www.ncbi.nlm.nih.gov/pubmed/27568360 | https://www.ncbi.nlm.nih.gov/pubmed/28242161 | https://www.drugbank.ca/drugs/DB09343

Tipiracil is a thymidine phosphorylase inhibitor, that used for the treatment of patients with metastatic colorectal cancer. Tipiracil is used in combination with trifluridine as Lonsurf. Trifluridine is incorporated into DNA via phosphorylation, ultimately inhibiting cell proliferation. Tipiracil increases systemic exposure of trifluridine when coadministered. Lonsurf has recently been approved for the treatment of adult patients with metastatic colorectal cancer (mCRC) who are refractory to or are not considered candidates for, current standard chemotherapy and biological therapy in the EU and USA and in unresectable advanced or recurrent CRC in Japan. The approved regimen of oral twice-daily Lonsurf significantly improved overall survival and progression-free survival and was associated with a significantly higher disease control rate than placebo when added to best supportive care in the multinational, pivotal phase III trial (RECOURSE) and a phase II Japanese trial. Trifluridine/tipiracil was associated with an acceptable tolerability profile, with adverse events generally being managed with dose reductions, temporary interruptions in treatment or administration of granulocyte-colony stimulating factor. The most common grade 3–4 adverse events (>10 %) were anemia, neutropenia, thrombocytopenia, and leukopenia.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Thymidine phosphorylase 2 Target ID: CHEMBL3106 Sources: https://www.ncbi.nlm.nih.gov/pubmed/14552762	Inhibitor 8504		20.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Metastatic colorectal cancer 14 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207981s000lbl.pdf	Primary		Approved 8583	LONSURF Approved Use LONSURF is indicated for the treatment of 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. LONSURF is a combination of trifluridine, a nucleoside metabolic inhibitor, and tipiracil, a thymidine phosphorylase inhibitor, indicated for the treatment of 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. (1) Launch Date 2015

C_max

Value	Dose	Co-administered	Analyte	Population
44.1 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22735906	30 mg/m² 1 times / day multiple, oral dose: 30 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: TRIFLURIDINE	TRIFLURIDINE	TIPIRACIL HYDROCHLORIDE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
41.8 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22735906	40 mg/m² 1 times / day multiple, oral dose: 40 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: TRIFLURIDINE	TRIFLURIDINE	TIPIRACIL HYDROCHLORIDE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
50.2 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22735906	50 mg/m² 1 times / day multiple, oral dose: 50 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: TRIFLURIDINE	TRIFLURIDINE	TIPIRACIL HYDROCHLORIDE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
99.6 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22735906	60 mg/m² 1 times / day multiple, oral dose: 60 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: TRIFLURIDINE	TRIFLURIDINE	TIPIRACIL HYDROCHLORIDE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
70 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22735906	70 mg/m² 1 times / day multiple, oral dose: 70 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: TRIFLURIDINE	TRIFLURIDINE	TIPIRACIL HYDROCHLORIDE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
234 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22735906	30 mg/m² 1 times / day multiple, oral dose: 30 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: TRIFLURIDINE	TRIFLURIDINE	TIPIRACIL HYDROCHLORIDE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
161 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22735906	40 mg/m² 1 times / day multiple, oral dose: 40 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: TRIFLURIDINE	TRIFLURIDINE	TIPIRACIL HYDROCHLORIDE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
300 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22735906	50 mg/m² 1 times / day multiple, oral dose: 50 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: TRIFLURIDINE	TRIFLURIDINE	TIPIRACIL HYDROCHLORIDE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
447 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22735906	60 mg/m² 1 times / day multiple, oral dose: 60 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: TRIFLURIDINE	TRIFLURIDINE	TIPIRACIL HYDROCHLORIDE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
317 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22735906	70 mg/m² 1 times / day multiple, oral dose: 70 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: TRIFLURIDINE	TRIFLURIDINE	TIPIRACIL HYDROCHLORIDE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
2.89 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22735906	30 mg/m² 1 times / day multiple, oral dose: 30 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: TRIFLURIDINE	TRIFLURIDINE	TIPIRACIL HYDROCHLORIDE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
1.82 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22735906	40 mg/m² 1 times / day multiple, oral dose: 40 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: TRIFLURIDINE	TRIFLURIDINE	TIPIRACIL HYDROCHLORIDE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
4.01 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22735906	50 mg/m² 1 times / day multiple, oral dose: 50 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: TRIFLURIDINE	TRIFLURIDINE	TIPIRACIL HYDROCHLORIDE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
2.21 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22735906	60 mg/m² 1 times / day multiple, oral dose: 60 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: TRIFLURIDINE	TRIFLURIDINE	TIPIRACIL HYDROCHLORIDE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
2.37 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22735906	70 mg/m² 1 times / day multiple, oral dose: 70 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: TRIFLURIDINE	TRIFLURIDINE	TIPIRACIL HYDROCHLORIDE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
2.4 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/207981s009lbl.pdf	35 mg/m² 2 times / day steady-state, oral dose: 35 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered:		TIPIRACIL HYDROCHLORIDE plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
92% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/207981s009lbl.pdf	35 mg/m² 2 times / day steady-state, oral dose: 35 mg/m² route of administration: Oral experiment type: STEADY-STATE co-administered:		TIPIRACIL HYDROCHLORIDE plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
			inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP 110 OCT2 779	CYP 303 OCT2 434	CYP1A2 832 CYP2B6 669 CYP3A4/5 133

Drug as perpetrator

Target	Modality	Activity
CYP 150	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207981Orig1s000ClinPharmR.pdf#page=34 Page: 34.0	no
CYP1A2 2333	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207981Orig1s000ClinPharmR.pdf#page=34 Page: 34.0	no
CYP2B6 1160	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207981Orig1s000ClinPharmR.pdf#page=34 Page: 34.0	no
CYP3A4/5 357	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207981Orig1s000ClinPharmR.pdf#page=34 Page: 34.0	no
OCT2 782	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207981Orig1s000ClinPharmR.pdf#page=34 Page: 34.0	yes

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
CYP 303	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207981Orig1s000ClinPharmR.pdf#page=34 Page: 34.0	no
OCT2 434	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207981Orig1s000ClinPharmR.pdf#page=34 Page: 34.0	yes		no (co-administration study) Comment: The population PK analysis suggested that concomitant administration of OCT2 inhibitors (n=24) had no effect on the PK parameters of trifluridine and tipiracil. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207981Orig1s000ClinPharmR.pdf#page=34 Page: 34.0

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2263	inhibitor 2237 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207981Orig1s000PharmR.pdf#page=102 Page: 102.0

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:90879	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:90879
ChemicalBook	CB62744247	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB62744247
MolPort	MolPort-006-168-519	https://www.molport.com/shop/molecule-link/MolPort-006-168-519
ZINC	ZINC000100032379	http://zinc15.docking.org/substances/ZINC000100032379

PubMed

Title	Date	PubMed
Repeated oral dosing of TAS-102 confers high trifluridine incorporation into DNA and sustained antitumor activity in mouse models.	2014-12	25230742
[Influence of the thymidine phosphorylase (platelet-derived endothelial cell growth factor) on tumor angiogenesis. Catalytic activity of enzyme inhibitors].	2010	20499682
Therapeutic potential of the dual-targeted TAS-102 formulation in the treatment of gastrointestinal malignancies.	2007-06	17441963
Thymidine phosphorylase from Escherichia coli: tight-binding inhibitors as enzyme active-site titrants.	2006-02	16570508
Cooperative stimulation of vascular endothelial growth factor expression by hypoxia and reactive oxygen species: the effect of targeting vascular endothelial growth factor and oxidative stress in an orthotopic xenograft model of bladder carcinoma.	2005-05-09	15841086
Pharmacokinetic modeling of species-dependent enhanced bioavailability of trifluorothymidine by thymidine phosphorylase inhibitor.	2004-06	15499188
Thymidine kinase and thymidine phosphorylase level as the main predictive parameter for sensitivity to TAS-102 in a mouse model.	2004-02	14719072
Crystal structure of human thymidine phosphorylase in complex with a small molecule inhibitor.	2004-01	14725767
Identification of a novel class of inhibitor of human and Escherichia coli thymidine phosphorylase by in silico screening.	2003-11-03	14552762
Significance of platelet-derived endothelial cell growth factor in the angiogenesis of human gastric cancer.	1998-02	9516932

Patents

Sample Use Guides

In Vivo Use Guide

In combination with trifluridine, 35 mg/m2 up to a maximum of 80 mg per dose (based on the trifluridine component) orally twice daily within one hour of completion of morning and evening meals on Days 1 through 5 and Days 8 through 12 of each 28-day cycle until disease progression or unacceptable toxicity.

Route of Administration: Oral

In Vitro Use Guide

HCT 116, HCT-15, and HT-29 cells were seeded at appropriate concentrations in duplicates in six-well plates. Twenty-four hours after plating, the cells were treated with the trifluridine (FTD 2 mkM or 4 mkM), or IR alone, or the combination of both using the RX-650 CABINET X-Ray system (Faxitron Xray Corp., Wheeling, IL, USA) with 3.4 Gy/min for 0.6-2.4 min. Ten to 12 days after plating, cells were fixed with 20% glutaraldehyde, stained with 0.05% crystal violet, and the number of colonies containing at least 50 cells was determined. Trifluridine enhances the efficacy of IR.

Substance Class	Chemical Created by `admin` on `Mon Mar 31 18:32:22 GMT 2025` Edited by `admin` on `Mon Mar 31 18:32:22 GMT 2025`
Record UNII	4H59KLQ0A4
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

TIPIRACIL HYDROCHLORIDE

Official Name

English

TAS-1-462

Preferred Name

English

TPI

Code

English

TIPIRACIL HYDROCHLORIDE [MI]

Common Name

English

Tipiracil hydrochloride [WHO-DD]

Common Name

English

LONSURF COMPONENT TIPIRACIL HYDROCHLORIDE

Common Name

English

TIPIRACIL HYDROCHLORIDE [JAN]

Common Name

English

TIPIRACIL HYDROCHLORIDE [ORANGE BOOK]

Common Name

English

5-CHLORO-6-(2-IMINO-PYRROLIDIN-1-YL)METHYL-2,4(1H,3H)-PYRIMIDINEDIONE HYDROCHLORIDE

Systematic Name

English

S-95005 COMPONENT TIPIRACIL HYDROCHLORIDE

Common Name

English

2,4(1H,3H)-PYRIMIDINEDIONE, 5-CHLORO-6-((2-IMINO-1-PYRROLIDINYL)METHYL)-, HYDROCHLORIDE (1:1)

Systematic Name

English

TIPIRACIL HYDROCHLORIDE [USAN]

Common Name

English

TAS-102 COMPONENT TIPIRACIL HYDROCHLORIDE

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C129825