You are using an unsupported browser. Please upgrade your browser to a newer version to get the best experience on DrugBank.
Identification
NameTrifluridine
Accession NumberDB00432  (APRD01275)
Typesmall molecule
Groupsapproved
Description

An antiviral derivative of thymidine used mainly in the treatment of primary keratoconjunctivitis and recurrent epithelial keratitis due to herpes simplex virus. (From Martindale, The Extra Pharmacopoeia, 30th ed, p557)

Structure
Thumb
Synonyms
SynonymLanguageCode
5-(Trifluoromethyl)deoxyuridineNot AvailableNot Available
5-Trifluoromethyl-2-deoxyuridineNot AvailableNot Available
F₃TNot AvailableIS
TFTNot AvailableINN
TrifluoromethyldeoxyuridineNot AvailableNot Available
TrifluorothymidineNot AvailableNot Available
TrifluridinGermanINN
TrifluridinaSpanishINN
TrifluridineFrenchINN
TrifluridinumLatinINN
SaltsNot Available
Brand names
NameCompany
ThilolPharmex
TriflumannDr. Gerhard Mann
TrifluridineAlcon
TriherpineMedivis
VirophtaHorus
ViropticMonarch
Brand mixturesNot Available
Categories
CAS number70-00-8
WeightAverage: 296.1999
Monoisotopic: 296.062006087
Chemical FormulaC10H11F3N2O5
InChI KeyVSQQQLOSPVPRAZ-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
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassOrganooxygen Compounds
ClassCarbohydrates and Carbohydrate Conjugates
SubclassGlycosyl Compounds
Direct parentPyrimidine 2'-deoxyribonucleosides and Analogues
Alternative parentsPentoses; Pyrimidones; Hydropyrimidines; Tetrahydrofurans; Oxolanes; Secondary Alcohols; Primary Alcohols; Ethers; Polyamines; Organofluorides; Alkyl Fluorides
Substituentspentose monosaccharide; pyrimidone; pyrimidine; monosaccharide; hydropyrimidine; tetrahydrofuran; oxolane; secondary alcohol; ether; primary alcohol; polyamine; organonitrogen compound; amine; organofluoride; organohalogen; alcohol; alkyl halide; alkyl fluoride
Classification descriptionThis compound belongs to the pyrimidine 2'-deoxyribonucleosides and analogues. These are compounds consisting of a pyrimidine linked to a ribose which lacks an hydroxyl group at position 2.
Pharmacology
IndicationOphthalmic solution for the treatment of primay keratoconjunctivitis and recurrent epithelial keratitis due to herpes simplex virus, types 1 and 2.
PharmacodynamicsTrifluridine is a fluorinated pyrimidine nucleoside with in vitro and in vivo activity against herpes simplex virus, types 1 and 2 and vacciniavirus. Some strains of adenovirus are also inhibited in vitro. Trifluridine is also effective in the treatment of epithelial keratitis that has not responded clinically to the topical administration of idoxuridine or when ocular toxicity or hypersensitivity to idoxuridine has occurred. In a smaller number of patients found to be resistant to topical vidarabine, trifluridine was also effective. Trifluridine interferes with DNA synthesis in cultured mammalian cells. However, its antiviral mechanism of action is not completely known.
Mechanism of actionThe mechanism of action of trifluridine has not been fully determined, but appears to involve the inhibition of viral replication. Trifluridine does this by incorporating into viral DNA during replication, which leads to the formation of defective proteins and an increased mutation rate. This drug also reversibly inhibits thymidylate synthetase, an enzyme that is necessary for DNA synthesis.
AbsorptionSystemic absorption of trifluridine following therapeutic dosing with trifluridine ophthalmic appears to be negligible.
Volume of distributionNot Available
Protein bindingNot Available
Metabolism

One major metabolite, 5-carboxy-2'-deoxyuridine found on the endothelial side of the cornea, indicating localized metabolism.

SubstrateEnzymesProduct
Trifluridine
Not Available
5-carboxy-2'-deoxyuridineDetails
Route of eliminationNot Available
Half lifeApproximately 12 to 18 minutes following ophthalmic administration.
ClearanceNot Available
ToxicityOverdosage by ocular instillation is unlikely because any excess solution should be quickly expelled from the conjunctival sac. Acute overdosage by accidental oral ingestion has not occurred. However, should such ingestion occur, the 75 mg dosage of trifluridine in a 7.5 mL bottle of trifluridine is not likely to produce adverse effects. Single intravenous doses of 1.5 to 30 mg/kg/day in children and adults with neoplastic disease produce reversible bone marrow depression as the only potentially serious toxic effect and only after three to five courses of therapy. The acute oral LD50 in the mouse and rat was 4379 mg/kg or higher.
Affected organisms
  • Human Herpes Virus
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
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 substrate Non-inhibitor 0.9071
CYP450 2D6 substrate Non-inhibitor 0.9231
CYP450 2C19 substrate Non-inhibitor 0.9025
CYP450 3A4 substrate 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
Pharmacoeconomics
Manufacturers
  • Alcon laboratories inc
  • Monarch pharmaceuticals inc
Packagers
Dosage forms
FormRouteStrength
SolutionOphthalmic
Prices
Unit descriptionCostUnit
Viroptic 1% Solution 7.5ml Bottle160.07USDbottle
Trifluridine 1% Solution 7.5ml Bottle153.4USDbottle
Trifluridine 1% eye drops19.69USDml
Viroptic 1% eye drops18.63USDml
Trifluridine 1 % opth soln15.21USDml
Sandoz Trifluridine 1 % Solution3.41USDml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point186-189 °CPhysProp
water solubility1560 mg/LNot Available
logP-0.46HANSCH,C ET AL. (1995)
pKa7.95SANGSTER (1994)
Predicted Properties
PropertyValueSource
water solubility6.69e+00 g/lALOGPS
logP-0.45ALOGPS
logP-0.75ChemAxon
logS-1.6ALOGPS
pKa (strongest acidic)7.6ChemAxon
pKa (strongest basic)-3ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count5ChemAxon
hydrogen donor count3ChemAxon
polar surface area99.1ChemAxon
rotatable bond count3ChemAxon
refractivity56.34ChemAxon
polarizability23.07ChemAxon
number of rings2ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis ReferenceNot Available
General Reference
  1. Costin D, Dogaru M, Popa AS, Cijevschi I: [Trifluridine therapy in herpetic in keratitis] Rev Med Chir Soc Med Nat Iasi. 2004 Apr-Jun;108(2):409-12. Pubmed
  2. Kuster P, Taravella M, Gelinas M, Stepp P: Delivery of trifluridine to human cornea and aqueous using collagen shields. CLAO J. 1998 Apr;24(2):122-4. Pubmed
  3. O’Brien WJ, Taylor JL: Therapeutic response of herpes simplex virus-induced corneal edema to trifluridine in combination with immunosuppressive agents. Invest Ophthalmol Vis Sci. 1991 Aug;32(9):2455-61. Pubmed
  4. 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. Pubmed
  5. 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. Pubmed
  6. 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. Pubmed
External Links
ResourceLink
KEGG DrugD00391
PubChem Compound6256
PubChem Substance46506192
ChemSpider6020
BindingDB50132298
Therapeutic Targets DatabaseDAP000760
PharmGKBPA451775
Drug Product Database2248529
RxListhttp://www.rxlist.com/cgi/generic2/trifluridine.htm
Drugs.comhttp://www.drugs.com/cdi/trifluridine-drops.html
WikipediaTrifluridine
ATC CodesS01AD02
AHFS Codes
  • 52:04.20
PDB EntriesNot Available
FDA labelNot Available
MSDSshow(55.2 KB)
Interactions
Drug InteractionsSearched, but no interactions found.
Food InteractionsNot Available

Targets

1. Thymidylate synthase

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Thymidylate synthase P04818 Details

References:

  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. De Clercq E: Antiviral drugs in current clinical use. J Clin Virol. 2004 Jun;30(2):115-33. Pubmed
  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. Epub 2009 Sep 29. Pubmed
  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. Pubmed
  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. Pubmed
  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. Pubmed
  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. Pubmed
  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. Pubmed
  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. Pubmed
  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. Pubmed
  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. Pubmed
  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. Pubmed
  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. Pubmed
  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. Pubmed
  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. Pubmed

2. DNA

Kind: nucleotide

Organism: Human

Pharmacological action: yes

Actions: other/unknown

Components

Name UniProt ID Details

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. Epub 2009 Sep 29. Pubmed
  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. Pubmed
  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. Pubmed
  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. Pubmed
  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. Pubmed
  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. Pubmed
  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. Pubmed
  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. Pubmed
  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. Pubmed
  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. Pubmed
  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. Pubmed

Enzymes

1. Thymidine kinase, cytosolic

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Thymidine kinase, cytosolic P04183 Details

References:

  1. 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. Pubmed
  2. 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. Pubmed
  3. Emura T, Nakagawa F, Fujioka A, Ohshimo H, Yokogawa T, Okabe H, Kitazato K: An optimal dosing schedule for a novel combination antimetabolite, TAS-102, based on its intracellular metabolism and its incorporation into DNA. Int J Mol Med. 2004 Feb;13(2):249-55. Pubmed
  4. 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. Pubmed

2. Thymidine phosphorylase

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Thymidine phosphorylase P19971 Details

References:

  1. 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. Pubmed
  2. 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. Pubmed
  3. 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. Pubmed
  4. 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. Pubmed
  5. 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. Pubmed
  6. 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. Pubmed

Transporters

1. Solute carrier family 22 member 6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Solute carrier family 22 member 6 Q4U2R8 Details

References:

  1. Wada S, Tsuda M, Sekine T, Cha SH, Kimura M, Kanai Y, Endou H: Rat multispecific organic anion transporter 1 (rOAT1) transports zidovudine, acyclovir, and other antiviral nucleoside analogs. J Pharmacol Exp Ther. 2000 Sep;294(3):844-9. Pubmed

Comments
comments powered by Disqus
Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:10