Trifluridine

Identification

Summary

Trifluridine is a nucleoside metabolic inhibitor used to treat keratoconjunctivitis and epithelial keratitis caused by simplex virus, and as a part of chemotherapy for certain types of metastatic gastrointestinal cancers.

Brand Names

Lonsurf, Viroptic

Generic Name

Trifluridine

DrugBank Accession Number

DB00432

Background

Trifluridine is a fluorinated pyrimidine nucleoside that is structurally related to idoxuridine ¹. It is an active antiviral agent in ophthalmic solutions used mainly in the treatment of primary keratoconjunctivitis and recurrent epithelial keratitis due to herpes simplex virus. It displays effective antiviral activity against Herpes simplex virus type 1 and 2 ¹.

The combination product of trifluridine with tipiracil marketed as Lonsurf has been approved in Japan, the United States, and the European Union 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. In the anticancer therapy, trifluridine acts as a thymidine-based nucleoside metabolic inhibitor that gets incorporated into DNA of cancer cells following cell uptake to aberrate DNA function during cell replication ¹⁰.

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Trifluridine (DB00432)

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Weight

Average: 296.1999
Monoisotopic: 296.062006087

Chemical Formula

C₁₀H₁₁F₃N₂O₅

Synonyms

• 5-(Trifluoromethyl)deoxyuridine
• 5-Trifluoromethyl-2-deoxyuridine
• F₃T
• TFT
• Trifluoromethyldeoxyuridine
• Trifluorothymidine
• Trifluorothymine deoxyriboside
• Trifluridin
• Trifluridina
• Trifluridine
• Trifluridinum

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Pharmacology

Indication

As a standalone product, trifluridine is used for the ophthalmic treatment of primay keratoconjunctivitis and recurrent epithelial keratitis due to herpes simplex virus, types 1 and 2.⁷

Trifluridine is also available as a combination product with tipiracil, which is indicated either alone or in combination with bevacizumab 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.⁸ This combination product is also used for adult patients with metastatic gastric or gastroesophageal junction adenocarcinoma and were 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.⁸

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Used in combination to treat	Metastatic colorectal cancer	Regimen in combination with: Bevacizumab (DB00112), Tipiracil (DB09343)	••••••••••••	•••••	•••••••• ••••••••• •••• ••••••••••••••••• ••••••••••• ••• ••••••••••• ••• ••••••••• •••• •••••••• •• ••••••••• •••••••• •••••••••• ••••••• •••• •••••••••	••••••
Used in combination to treat	Metastatic colorectal cancer	Combination Product in combination with: Tipiracil (DB09343)	••••••••••••	•••••	•••••••••• ••••••• •••• •••••••••• ••• ••••••••• •••• •••••••• •• ••••••••• •••••••• •••••••• ••••••••• •••• ••••••••••••••••• ••••••••••• ••• ••••••••••	••••••
Used in combination to treat	Metastatic gastric cancers	Combination Product in combination with: Tipiracil (DB09343)	••••••••••••	•••••	•••••••• ••••••••• •••• •• ••••••••••••••• •••••••• •••••••• •••••••••••••• ••••••••••••• •••••••••• ••••••• •••• •••••••••••••••• ••••••••••••• •••••••• •••••• •• •••••••••••••••• ••••••••••••• ••••• •• ••••• •• •••••••• •••••••	••••••
Used in combination to treat	Metastatic gastroesophageal junction adenocarcinoma	Combination Product in combination with: Tipiracil (DB09343)	••••••••••••	•••••	•••••••• •••••••••••••• ••••••••••••• •••••••• ••••••••• •••• •• ••••••••••••••• •••••••• •••••••••• ••••••• •••• •••••••••••••••• ••••••••••••• ••••• •• ••••• •• •••••••• •••••••• •••••••• •••••• •• •••••••••••••••• ••••••••••••	••••••
Treatment of	Primary keratoconjunctivitis caused by herpes simplex virus type 1		••••••••••••			•••••••••

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Pharmacodynamics

Trifluridine exhibits an antiviral effect against herpes simplex virus, types 1 and 2 and vacciniavirus both in vitro and in vivo ¹. Some strains of adenovirus that contribute to the pathology of keratoconjunctivitis were shown to be susceptible to trifluridine in vitro ¹. While there is evidence from a study that cross-resistance may develop between trifluridine and idoxuridine or vidarabine, trifluridine was shown to effective in treating dendritic ulcers in patients with herpetic keratitis who are unresponsive to idoxuridine or vidarabine based on the results from masked comparative trials ¹. In nonclinical studies, trifluridine/tipiracil hydrochloride demonstrated antitumour activity against both 5-fluorouracil (5-FU) sensitive and resistant colorectal cancer cell lines ¹⁰. The cytotoxic activity of trifluridine and tipiracil against several human tumour xenografts show high correlation with the amount of trifluridine incorporated into DNA, indicating that the primary mechanism of action of trifluridine involves the direct incorporation into the cancer cell DNA ¹⁰. Trifluridine and tipiracil demonstrated anti-tumor activity against KRAS wild-type and mutant human colorectal cancer xenografts in mice ^Label.

In clinical studies comprised of patients with previously treated metastatic colorectal cancer, treatment of trifluridine in combination with tipiracil in addition to best supportive care over a 5- or 7-month period resulted in increased progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) compared to placebo ¹⁰. In an open-label study, administration of trifluridine at the recommended dosage in patients with advanced solid tumors had no clinically relevant effect on QT/QTc prolongation compared with placebo ^Label. Two out of 48 patients displayed had QTc greater than 500 msec and 1 of 42 patients (2.4%) had a QTc increase from baseline greater than 60 msec ^Label.

Mechanism of action

The mechanism of action of trifluridine as an antiviral agent has not been fully elucidated, but appears to involve the inhibition of viral replication. Trifluridine gets incorporated into viral DNA during replication, which leads to the formation of defective proteins and an increased mutation rate. Trifluridine also mediates antineoplastic activities via this mechanism; following uptake into cancer cells, trifluridine is rapidly phosphorylated by thymidine kinase to its active monophosphate form ². Subsequent phosphorylation produces trifluridine triphosphate ², which is readily incorporated into the DNA of tumour cells in place of thymidine bases to perturb DNA function, DNA synthesis, and tumour cell proliferation ^Label. As trifluridine is subject to rapid degradation by TPase and readily metabolised by a first-pass effect following oral administration, tipiracil is added in the antineoplastic combination product as an inhibitor of TPase to increase the bioavailability of trifluridine ¹⁰. Trifluridine monophosphate also reversibly inhibits thymidylate synthetase (TS), an enzyme that is necessary for DNA synthesis and which levels are shown to be elevated different cancer cell lines ³. Up-regulation of the expression of the TS enzyme may also lead to the resistance to antineoplastic therapies, such as 5-fluorouracil (5-FU). [A35289 However, this inhibitory effect is not considered to be sufficient enough to fully contribute to the cytotoxicity in cancer cells. ²

Target	Actions	Organism
ADNA	other/unknown	Humans
AThymidylate synthase	inhibitor	Humans

Absorption

After oral administration of LONSURF with [14C]-trifluridine, at least 57% of the administered trifluridine was absorbed. Following a single dose of LONSURF (35 mg/m²) in patients with advanced solid tumors, the mean times to peak plasma concentrations (T_max) of trifluridine was around 2 hours.⁹ Trifluridine area under the concentration-time curve from time 0 to the last measurable concentration (AUC_0-last) was approximately 3-fold higher and maximum concentration (C_max) was approximately 2-fold higher after multiple dose administration (twice daily for 5 days a week with 2 days rest for 2 weeks followed by a 14-day rest, repeated every 4 weeks) than after single-dose administration.⁹

Following a single oral administration of LONSURF at 35 mg/m² in patients with cancer, the mean time to peak plasma concentration (T_max) of trifluridine was around 2 hours.⁸ For the ophthalmic formulation, systemic absorption appears to be negligible.⁷ A standardized high-fat, high-calorie meal decreased trifluridine C_max by approximately 40% but did not change trifluridine AUC compared to those in a fasting state in patients with cancer following administration of a single dose of LONSURF 35 mg/m².⁷

In a dose finding study (15 to 35 mg/m² twice daily), the AUC from time 0 to 10 hours (AUC0-10) of trifluridine tended to increase more than expected based on the increase in dose.⁹

Volume of distribution

Following a single dose of LONSURF (35 mg/m²) in patients with advanced solid tumours, the apparent volume of distribution (Vd/F) for trifluridine was 21 L.⁹

Protein binding

In vitro findings suggest that the protein binding of trifluridine in human plasma is greater than 96%, where it is mainly bound to human serum albumin. Protein binding of trifluridine is independent of drug concentration and presence of tipiracil.⁸

Metabolism

Trifluridine is not metabolized by cytochrome P450 (CYP) enzymes. Trifluridine is mainly eliminated by metabolism via thymidine phosphorylase to form an inactive metabolite, 5-(trifluoromethyl) uracil (FTY). No other major metabolites were detected in plasma or urine.⁸ Other minor metabolites, such as 5-carboxy-2'-deoxyuridine found on the endothelial side of the cornea or 5-carboxyuraci, were also detected, but only at low or trace level in plasma and urine.^4,9

Hover over products below to view reaction partners

• Trifluridine
  • 5-carboxy-2'-deoxyuridine
  • 5-(trifluoromethyl) uracil

Route of elimination

After single oral administration of LONSURF (60 mg) with [14C]-trifluridine, the total cumulative excretion of radioactivity was 60% of the administered dose. The majority of recovered radioactivity was eliminated into urine (55% of the dose) as FTY and trifluridine glucuronide isomers within 24 hours and the excretion into feces and expired air was <3% for both. The unchanged trifluridine was <3% of administered dose recovered in the urine and feces.⁸

Half-life

After administration of LONSURF 35 mg/m², the mean elimination and steady-state half-life (t_1/2) of trifluridine was 1.4 hours and 2.1 hours respectively.⁸ For the ophthalmic formulation, the half-life is significantly shorter, approximately only 12 minutes.⁷

Clearance

Following a single dose of LONSURF (35 mg/m²) in patients with advanced solid tumours, the oral clearance (CL/F) for trifluridine was 10.5 L/hr.⁹

Adverse Effects

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Toxicity

Intravenous LD50 in rat was 2946 mg/kg ^MSDS. Oral LD50 in rat and mouse were > 4379mg/kg ^MSDS. Overdosage via ocular instillation is unlikely. The highest dose of orally-administered Lonsurf, trifluridine in combination with tipiracil, administered in clinical studies was 180 mg/m^2 per day. The primary anticipated complication of an overdose is bone marrow suppression. There is no known antidote for trifluridine overdose: in case of an overdose, management should include customary therapeutic and supportive medical intervention aimed at correcting the presenting clinical manifestations and preventing their possible complications ¹⁰. Based on the findings from animal studies, trifluridine may cause fetal toxicity when administered to pregnant patients ¹⁰.

Pathways

Not Available

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Interactions

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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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Abacavir	Trifluridine may decrease the excretion rate of Abacavir which could result in a higher serum level.
Abatacept	The risk or severity of adverse effects can be increased when Trifluridine is combined with Abatacept.
Aceclofenac	Aceclofenac may decrease the excretion rate of Trifluridine which could result in a higher serum level.
Acemetacin	Acemetacin may decrease the excretion rate of Trifluridine which could result in a higher serum level.
Acetaminophen	Acetaminophen may decrease the excretion rate of Trifluridine which could result in a higher serum level.

Food Interactions

• Take with food.

Products

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International/Other Brands

Thilol (Pharmex) / Triflumann (Dr. Gerhard Mann) / Triherpine (Medivis) / Virophta (Horus)

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Viroptic	Solution	1 %	Ophthalmic	Bausch & Lomb Inc	1987-12-31	Not applicable
Viroptic	Solution	1 g/100mL	Ophthalmic	Pfizer Laboratories Div Pfizer Inc	1980-04-10	2018-04-03
Viroptic	Solution	1 g/100mL	Ophthalmic	Physicians Total Care, Inc.	1980-04-10	2012-06-30

Generic Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Apo-trifluridine Ophthalmic Solution	Solution	1 %	Ophthalmic	Apotex Corporation	Not applicable	Not applicable
Sandoz Trifluridine	Solution	1 %	Ophthalmic	Sandoz Canada Incorporated	2004-01-23	2019-08-01
Trifluridine	Solution	1 g/100mL	Ophthalmic	Greenstone LLC	1980-04-10	2018-06-05
Trifluridine	Solution	10 mg/1mL	Ophthalmic	Sandoz Inc	2001-05-14	Not applicable
Trifluridine	Solution / drops	10 mg/1mL	Ophthalmic	Hi-Tech Pharmacal Co., Inc.	2017-07-28	Not applicable

Mixture Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End	Region	Image
Lonsurf	Trifluridine (20 mg) + Tipiracil hydrochloride (8.19 mg)	Tablet, film coated	Oral	Les Laboratoires Servier	2016-09-08	Not applicable
Lonsurf	Trifluridine (15 mg) + Tipiracil hydrochloride (6.14 mg)	Tablet, film coated	Oral	Les Laboratoires Servier	2016-09-08	Not applicable
LONSURF	Trifluridine (20 MG) + Tipiracil (8.19 MG)	Tablet, film coated	Oral	Les Laboratoires Servier	2016-09-22	Not applicable
LONSURF	Trifluridine (15 MG) + Tipiracil (6.14 MG)	Tablet, film coated	Oral	Les Laboratoires Servier	2016-09-22	Not applicable
Lonsurf	Trifluridine (15 mg) + Tipiracil hydrochloride (6.14 mg)	Tablet	Oral	Taiho Pharma Canada, Inc.	2018-03-22	Not applicable

Categories

ATC Codes

L01BC59 — Trifluridine, combinations

• L01BC — Pyrimidine analogues
• L01B — ANTIMETABOLITES
• L01 — ANTINEOPLASTIC AGENTS
• L — ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

S01AD02 — Trifluridine

• S01AD — Antivirals
• S01A — ANTIINFECTIVES
• S01 — OPHTHALMOLOGICALS
• S — SENSORY ORGANS

Drug Categories

• Anti-Infective Agents
• Antimetabolites
• Antineoplastic Agents
• Antineoplastic and Immunomodulating Agents
• Antiviral Agents
• Deoxyribonucleosides
• Drugs that are Mainly Renally Excreted
• Immunosuppressive Agents
• Noxae
• Nucleic Acid Synthesis Inhibitors
• Nucleic Acids, Nucleotides, and Nucleosides
• Nucleoside Analog Antiviral
• Nucleoside Metabolic Inhibitor
• Nucleosides
• OAT1/SLC22A6 inhibitors
• OAT1/SLC22A6 Substrates
• OAT3/SLC22A8 Substrates
• Ophthalmologicals
• Pyrimidine Analogues
• Pyrimidine Nucleosides
• Pyrimidines
• Sensory Organs
• Toxic Actions

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as pyrimidine 2'-deoxyribonucleosides. These are compounds consisting of a pyrimidine linked to a ribose which lacks a hydroxyl group at position 2.

Kingdom

Organic compounds

Super Class

Nucleosides, nucleotides, and analogues

Class

Pyrimidine nucleosides

Sub Class

Pyrimidine 2'-deoxyribonucleosides

Direct Parent

Pyrimidine 2'-deoxyribonucleosides

Alternative Parents

Pyrimidones / Hydroxypyrimidines / Hydropyrimidines / Tetrahydrofurans / Heteroaromatic compounds / Secondary alcohols / Oxacyclic compounds / Azacyclic compounds / Primary alcohols / Organopnictogen compounds / Organonitrogen compounds / Organofluorides / Organic oxides / Hydrocarbon derivatives / Alkyl fluorides

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Substituents

Alcohol / Alkyl fluoride / Alkyl halide / Aromatic heteromonocyclic compound / Azacycle / Heteroaromatic compound / Hydrocarbon derivative / Hydropyrimidine / Hydroxypyrimidine / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organofluoride / Organohalogen compound / Organoheterocyclic compound / Organonitrogen compound / Organooxygen compound / Organopnictogen compound / Oxacycle / Primary alcohol / Pyrimidine / Pyrimidine 2'-deoxyribonucleoside / Pyrimidone / Secondary alcohol / Tetrahydrofuran

show 15 more

Molecular Framework

Aromatic heteromonocyclic compounds

External Descriptors

organofluorine compound, nucleoside analogue, pyrimidine 2'-deoxyribonucleoside (CHEBI:75179)

Affected organisms

• Human Herpes Virus

Chemical Identifiers

UNII

RMW9V5RW38

CAS number

70-00-8

InChI Key

VSQQQLOSPVPRAZ-RRKCRQDMSA-N

InChI

InChI=1S/C10H11F3N2O5/c11-10(12,13)4-2-15(9(19)14-8(4)18)7-1-5(17)6(3-16)20-7/h2,5-7,16-17H,1,3H2,(H,14,18,19)/t5-,6+,7+/m0/s1

IUPAC Name

1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-(trifluoromethyl)-1,2,3,4-tetrahydropyrimidine-2,4-dione

SMILES

OC[C@H]1O[C@H](C[C@@H]1O)N1C=C(C(=O)NC1=O)C(F)(F)F

References

General References

1. Carmine AA, Brogden RN, Heel RC, Speight TM, Avery GS: Trifluridine: a review of its antiviral activity and therapeutic use in the topical treatment of viral eye infections. Drugs. 1982 May;23(5):329-53. [Article]
2. Burness CB, Duggan ST: Trifluridine/Tipiracil: A Review in Metastatic Colorectal Cancer. Drugs. 2016 Sep;76(14):1393-402. doi: 10.1007/s40265-016-0633-9. [Article]
3. Matsuoka K, Nakagawa F, Kobunai T, Takechi T: Trifluridine/tipiracil overcomes the resistance of human gastric 5-fluorouracil-refractory cells with high thymidylate synthase expression. Oncotarget. 2018 Feb 5;9(17):13438-13450. doi: 10.18632/oncotarget.24412. eCollection 2018 Mar 2. [Article]
4. Pavan-Langston D, Nelson DJ: Intraocular penetration of trifluridine. Am J Ophthalmol. 1979 Jun;87(6):814-8. [Article]
5. Altmann S, Brandt CR, Murphy CJ, Patnaikuni R, Takla T, Toomey M, Nesbit B, McIntyre K, Covert J, Dubielzig R, Leatherberry G, Adkins E, Kodihalli S: Evaluation of therapeutic interventions for vaccinia virus keratitis. J Infect Dis. 2011 Mar 1;203(5):683-90. doi: 10.1093/infdis/jiq103. Epub 2011 Jan 28. [Article]
6. FDA Approved Drug Products: LONSURF (trifluridine and tipiracil) tablets, for oral use [Link]
7. FDA Approved Drug Products: TRIFLURIDINE solution for ophthalmic use [Link]
8. FDA Approved Drug Products: LONSURF (trifluridine and tipiracil) tablets, for oral use (August 2023) [Link]
9. EMA Product Information: LONSURF (trifluridine and tipiracil) tablets, for oral use [Link]
10. Lonsurf Summary of Product Characteristics- European Medicines Agency - Europa EU [File]
11. DailyMed Label: VIROPTIC® Ophthalmic Solution, 1% Sterile (trifluridine ophthalmic solution) [File]

External Links

Human Metabolome Database

HMDB0014576

KEGG Drug

D00391

PubChem Compound

6256

PubChem Substance

46506192

ChemSpider

6020

BindingDB

50132298

RxNav

10803

ChEBI

75179

ChEMBL

CHEMBL1129

ZINC

ZINC000003842753

Therapeutic Targets Database

DAP000760

PharmGKB

PA451775

RxList

RxList Drug Page

Drugs.com

Drugs.com Drug Page

Wikipedia

Trifluridine

FDA label

Download (490 KB)

MSDS

Download (50.8 KB)

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
3	Active Not Recruiting	Treatment	Colorectal Cancer	3
3	Active Not Recruiting	Treatment	Colorectal Neoplasms	1
3	Active Not Recruiting	Treatment	Metastatic Colorectal Cancer (CRC)	1
3	Completed	Treatment	Metastatic Colorectal Cancer (CRC)	1
3	Completed	Treatment	Refractory, metastatic Colorectal cancer	1

Pharmacoeconomics

Manufacturers

• Alcon laboratories inc
• Monarch pharmaceuticals inc

Packagers

• Alcon Laboratories
• DSM Corp.
• Falcon Pharmaceuticals Ltd.
• Monarch Pharmacy
• Pharmedix
• Physicians Total Care Inc.
• Professional Compounding Centers America LLC
• Watson Pharmaceuticals

Dosage Forms

Form	Route	Strength
Tablet	Oral
Tablet, film coated	Oral
Solution	Ophthalmic	10 mg/1mL
Solution / drops	Ophthalmic	10 mg/1mL
Ointment	Topical	10 mg
Solution / drops	Ophthalmic
Solution	Conjunctival; Ophthalmic	10 mg
Solution	Ophthalmic	1 %
Solution	Ophthalmic	1 g/100mL

Prices

Unit description	Cost	Unit
Viroptic 1% Solution 7.5ml Bottle	160.07USD	bottle
Trifluridine 1% Solution 7.5ml Bottle	153.4USD	bottle
Trifluridine 1% eye drops	19.69USD	ml
Viroptic 1% eye drops	18.63USD	ml
Trifluridine 1 % opth soln	15.21USD	ml
Sandoz Trifluridine 1 % Solution	3.41USD	ml

DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.

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
US10960004	No	2021-03-30	2037-02-03
US9943537	No	2018-04-17	2034-09-05

Properties

State

Solid

Experimental Properties

Property	Value	Source
melting point (°C)	186-189	PhysProp
water solubility	Soluble	MSDS
logP	-0.46	HANSCH,C ET AL. (1995)
pKa	7.95	SANGSTER (1994)

Predicted Properties

Property	Value	Source
Water Solubility	6.69 mg/mL	ALOGPS
logP	-0.45	ALOGPS
logP	-0.75	Chemaxon
logS	-1.6	ALOGPS
pKa (Strongest Acidic)	8.5	Chemaxon
pKa (Strongest Basic)	-3	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	5	Chemaxon
Hydrogen Donor Count	3	Chemaxon
Polar Surface Area	99.1 Å2	Chemaxon
Rotatable Bond Count	3	Chemaxon
Refractivity	56.34 m3·mol-1	Chemaxon
Polarizability	23.55 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

Property	Value	Probability
Human Intestinal Absorption	+	0.9636
Blood Brain Barrier	+	0.7348
Caco-2 permeable	-	0.8782
P-glycoprotein substrate	Non-substrate	0.7103
P-glycoprotein inhibitor I	Non-inhibitor	0.8788
P-glycoprotein inhibitor II	Non-inhibitor	0.8078
Renal organic cation transporter	Non-inhibitor	0.9088
CYP450 2C9 substrate	Non-substrate	0.7706
CYP450 2D6 substrate	Non-substrate	0.8588
CYP450 3A4 substrate	Non-substrate	0.5276
CYP450 1A2 substrate	Non-inhibitor	0.9046
CYP450 2C9 inhibitor	Non-inhibitor	0.9071
CYP450 2D6 inhibitor	Non-inhibitor	0.9231
CYP450 2C19 inhibitor	Non-inhibitor	0.9025
CYP450 3A4 inhibitor	Non-inhibitor	0.8903
CYP450 inhibitory promiscuity	Low CYP Inhibitory Promiscuity	0.8652
Ames test	AMES toxic	0.9108
Carcinogenicity	Non-carcinogens	0.7552
Biodegradation	Not ready biodegradable	0.9698
Rat acute toxicity	2.4696 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.9897
hERG inhibition (predictor II)	Non-inhibitor	0.7454

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted GC-MS Spectrum - GC-MS	Predicted GC-MS	splash10-002f-9070000000-5b0bc8f23d4e75143939
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0a4j-0090000000-ab5fcfff44302c75169b
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0002-0090000000-29274348cb9fb3333727
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-01pk-7900000000-da39d725617ebd7d33f1
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-00n0-1970000000-c5de29c967465d2a8d4b
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0r00-0590000000-9ea67cbe3b3d0426c103
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-002f-7920000000-effccb223ba81d21c6ba
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å2)	Source type	Source
[M-H]-	165.3156645	predicted	DarkChem Lite v0.1.0
[M-H]-	165.69609	predicted	DeepCCS 1.0 (2019)
[M+H]+	165.4855645	predicted	DarkChem Lite v0.1.0
[M+H]+	168.09166	predicted	DeepCCS 1.0 (2019)
[M+Na]+	165.4976645	predicted	DarkChem Lite v0.1.0
[M+Na]+	174.31265	predicted	DeepCCS 1.0 (2019)

Targets

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Details1. DNA

Kind

Nucleotide

Organism

Humans

Pharmacological action

Yes

Actions

Other/unknown

DNA is the molecule of heredity, as it is responsible for the genetic propagation of most inherited traits. It is a polynucleic acid that carries genetic information on cell growth, division, and function. DNA consists of two long strands of nucleotides twisted into a double helix and held together by hydrogen bonds. The sequence of nucleotides determines hereditary characteristics. Each strand serves as the template for subsequent DNA replication and as a template for mRNA production, leading to protein synthesis via ribosomes.

References

1. Bijnsdorp IV, Kruyt FA, Fukushima M, Smid K, Gokoel S, Peters GJ: Molecular mechanism underlying the synergistic interaction between trifluorothymidine and the epidermal growth factor receptor inhibitor erlotinib in human colorectal cancer cell lines. Cancer Sci. 2010 Feb;101(2):440-7. doi: 10.1111/j.1349-7006.2009.01375.x. Epub 2009 Sep 29. [Article]
2. Bijnsdorp IV, Peters GJ, Temmink OH, Fukushima M, Kruyt FA: Differential activation of cell death and autophagy results in an increased cytotoxic potential for trifluorothymidine compared to 5-fluorouracil in colon cancer cells. Int J Cancer. 2010 May 15;126(10):2457-68. doi: 10.1002/ijc.24943. [Article]
3. Bijnsdorp IV, Kruyt FA, Fukushima M, Peters GJ: Trifluorothymidine induces cell death independently of p53. Nucleosides Nucleotides Nucleic Acids. 2008 Jun;27(6):699-703. doi: 10.1080/15257770802145017. [Article]
4. Madeira VM, Antunes-Madeira MC: Chemical composition of sarcolemma isolated from rabbit skeletal muscle. Biochim Biophys Acta. 1973 Mar 16;298(2):230-8. [Article]
5. Temmink OH, Hoogeland MF, Fukushima M, Peters GJ: Low folate conditions may enhance the interaction of trifluorothymidine with antifolates in colon cancer cells. Cancer Chemother Pharmacol. 2006 Jan;57(2):171-9. Epub 2005 Jul 12. [Article]
6. Oberg B, Johansson NG: The relative merits and drawbacks of new nucleoside analogues with clinical potential. J Antimicrob Chemother. 1984 Aug;14 Suppl A:5-26. [Article]
7. Emura T, Nakagawa F, Fujioka A, Ohshimo H, Kitazato K: Thymidine kinase and thymidine phosphorylase level as the main predictive parameter for sensitivity to TAS-102 in a mouse model. Oncol Rep. 2004 Feb;11(2):381-7. [Article]
8. Overman MJ, Kopetz S, Varadhachary G, Fukushima M, Kuwata K, Mita A, Wolff RA, Hoff P, Xiong H, Abbruzzese JL: Phase I clinical study of three times a day oral administration of TAS-102 in patients with solid tumors. Cancer Invest. 2008 Oct;26(8):794-9. doi: 10.1080/07357900802087242. [Article]
9. Hong DS, Abbruzzese JL, Bogaard K, Lassere Y, Fukushima M, Mita A, Kuwata K, Hoff PM: Phase I study to determine the safety and pharmacokinetics of oral administration of TAS-102 in patients with solid tumors. Cancer. 2006 Sep 15;107(6):1383-90. [Article]
10. Temmink OH, Prins HJ, van Gelderop E, Peters GJ: The Hollow Fibre Assay as a model for in vivo pharmacodynamics of fluoropyrimidines in colon cancer cells. Br J Cancer. 2007 Jan 15;96(1):61-6. Epub 2006 Dec 19. [Article]
11. Bassler R, Buchwald W: [Experimental inflammation and fibrosis of the lung framework caused by ionizing rays. Light and electron microscopic studies]. Fortschr Geb Rontgenstr Nuklearmed. 1966 Feb;104(2):192-206. [Article]

Details2. Thymidylate synthase

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

General Function

Thymidylate synthase activity

Specific Function

Contributes to the de novo mitochondrial thymidylate biosynthesis pathway.

Gene Name

TYMS

Uniprot ID

P04818

Uniprot Name

Thymidylate synthase

Molecular Weight

35715.65 Da

References

1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
2. De Clercq E: Antiviral drugs in current clinical use. J Clin Virol. 2004 Jun;30(2):115-33. [Article]
3. Bijnsdorp IV, Kruyt FA, Fukushima M, Smid K, Gokoel S, Peters GJ: Molecular mechanism underlying the synergistic interaction between trifluorothymidine and the epidermal growth factor receptor inhibitor erlotinib in human colorectal cancer cell lines. Cancer Sci. 2010 Feb;101(2):440-7. doi: 10.1111/j.1349-7006.2009.01375.x. Epub 2009 Sep 29. [Article]
4. Bijnsdorp IV, Peters GJ, Temmink OH, Fukushima M, Kruyt FA: Differential activation of cell death and autophagy results in an increased cytotoxic potential for trifluorothymidine compared to 5-fluorouracil in colon cancer cells. Int J Cancer. 2010 May 15;126(10):2457-68. doi: 10.1002/ijc.24943. [Article]
5. Bijnsdorp IV, Kruyt FA, Fukushima M, Peters GJ: Trifluorothymidine induces cell death independently of p53. Nucleosides Nucleotides Nucleic Acids. 2008 Jun;27(6):699-703. doi: 10.1080/15257770802145017. [Article]
6. Madeira VM, Antunes-Madeira MC: Chemical composition of sarcolemma isolated from rabbit skeletal muscle. Biochim Biophys Acta. 1973 Mar 16;298(2):230-8. [Article]
7. Temmink OH, Hoogeland MF, Fukushima M, Peters GJ: Low folate conditions may enhance the interaction of trifluorothymidine with antifolates in colon cancer cells. Cancer Chemother Pharmacol. 2006 Jan;57(2):171-9. Epub 2005 Jul 12. [Article]
8. Oberg B, Johansson NG: The relative merits and drawbacks of new nucleoside analogues with clinical potential. J Antimicrob Chemother. 1984 Aug;14 Suppl A:5-26. [Article]
9. Temmink OH, Comijn EM, Fukushima M, Peters GJ: Intracellular thymidylate synthase inhibition by trifluorothymidine in FM3A cells. Nucleosides Nucleotides Nucleic Acids. 2004 Oct;23(8-9):1491-4. [Article]
10. Shintani M, Urano M, Takakuwa Y, Kuroda M, Kamoshida S: Immunohistochemical characterization of pyrimidine synthetic enzymes, thymidine kinase-1 and thymidylate synthase, in various types of cancer. Oncol Rep. 2010 May;23(5):1345-50. [Article]
11. Emura T, Nakagawa F, Fujioka A, Ohshimo H, Kitazato K: Thymidine kinase and thymidine phosphorylase level as the main predictive parameter for sensitivity to TAS-102 in a mouse model. Oncol Rep. 2004 Feb;11(2):381-7. [Article]
12. Overman MJ, Kopetz S, Varadhachary G, Fukushima M, Kuwata K, Mita A, Wolff RA, Hoff P, Xiong H, Abbruzzese JL: Phase I clinical study of three times a day oral administration of TAS-102 in patients with solid tumors. Cancer Invest. 2008 Oct;26(8):794-9. doi: 10.1080/07357900802087242. [Article]
13. Hong DS, Abbruzzese JL, Bogaard K, Lassere Y, Fukushima M, Mita A, Kuwata K, Hoff PM: Phase I study to determine the safety and pharmacokinetics of oral administration of TAS-102 in patients with solid tumors. Cancer. 2006 Sep 15;107(6):1383-90. [Article]
14. Temmink OH, Prins HJ, van Gelderop E, Peters GJ: The Hollow Fibre Assay as a model for in vivo pharmacodynamics of fluoropyrimidines in colon cancer cells. Br J Cancer. 2007 Jan 15;96(1):61-6. Epub 2006 Dec 19. [Article]
15. Bassler R, Buchwald W: [Experimental inflammation and fibrosis of the lung framework caused by ionizing rays. Light and electron microscopic studies]. Fortschr Geb Rontgenstr Nuklearmed. 1966 Feb;104(2):192-206. [Article]

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Drug created at June 13, 2005 13:24 / Updated at February 20, 2024 23:55