Chemistry:Trifluridine

Short description: Chemical compound

Trifluridine

Clinical data
Trade names	Viroptic; Lonsurf (+tipiracil)
Other names	α,α,α-trifluorothymidine; 5-trifluromethyl-2′-deoxyuridine; FTD5-trifluoro-2′-deoxythymidine; TFT; CF3dUrd; FTD; F3TDR; F3Thd
AHFS/Drugs.com	Monograph
License data	EU EMA: by INN
Pregnancy category	US: C (Risk not ruled out)
Routes of administration	Eye drops; tablets (+tipiracil)
ATC code	S01AD02 (WHO) L01BC59 (WHO)
Legal status
Legal status	CA: ℞-only US: ℞-only
Pharmacokinetic data
Bioavailability	Negligible (eye drops); ≥57% (oral)
Protein binding	>96%
Metabolism	Thymidine phosphorylase
Elimination half-life	12 minutes (eye drops); 1.4–2.1 hrs (combination with tipiracil)
Excretion	Mostly via urine
Identifiers
IUPAC name 1-[4-Hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-(trifluoromethyl)-(1H,3H)-pyrimidine-2,4-dione
CAS Number	70-00-8 Y
PubChem CID	6256
DrugBank	DB00432 Y
ChemSpider	6020 Y
UNII	RMW9V5RW38
KEGG	D00391 Y
ChEBI	CHEBI:75179 N
ChEMBL	ChEMBL1129 Y
Chemical and physical data
Formula	C10H11F3N2O5
Molar mass	296.202 g·mol−1
3D model (JSmol)	Interactive image
SMILES FC(F)(F)C=1C(=O)NC(=O)N(C=1)[C@@H]2O[C@@H]([C@@H](O)C2)CO
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 Y Key:VSQQQLOSPVPRAZ-RRKCRQDMSA-N Y
NY (what is this?)  (verify)

Trifluridine (also called trifluorothymidine; abbreviation TFT or FTD) is an anti-herpesvirus antiviral drug, used primarily on the eye. It was sold under the trade name Viroptic by Glaxo Wellcome, now merged into GlaxoSmithKline. The brand is now owned by Monarch Pharmaceuticals, which is wholly owned by King Pharmaceuticals.

Trifluridine was approved for medical use in 1980. It is also a component of the anti-cancer drug trifluridine/tipiracil, which is taken by mouth.

Medical uses

Trifluridine eye drops are used for the treatment of keratitis and keratoconjunctivitis caused by the herpes simplex virus types 1 and 2, as well as for prevention and treatment of vaccinia virus infections of the eye.

A Cochrane Systematic Review showed that trifluridine and aciclovir were a more effective treatment than idoxuridine or vidarabine, significantly increasing the relative number of successfully healed eyes in one to two weeks.

For cancer treatment, the combination trifluridine/tipiracil is used.

Adverse effects

Common side effects of trifluridine eye drops include transient burning, stinging, local irritation, and edema of the eyelids.

Adverse effects of the anti-cancer formulation have only been evaluated for the combination trifluridine/tipiracil, not for the individual components.

Interactions

Only in vitro interaction studies are available. In these, trifluridine used the concentrative nucleoside transporter 1 (CNT1) and equilibrative nucleoside transporters 1 (ENT1) and 2 (ENT2). Drugs that interact with these transporters could influence blood plasma concentrations of trifluridine. Being a thymidine phosphorylase inhibitor, trifluridine could also interact with substrates of this enzyme such as zidovudine.

For the eye drops, trifluridine absorption is negligible, rendering interactions basically irrelevant.

Pharmacology

Mechanism of action (eye drops)

It is a nucleoside analogue, a modified form of deoxyuridine, similar enough to be incorporated into viral DNA replication, but the –CF₃ group added to the uracil component blocks base pairing, thus interfering with viral DNA replication.

Pharmacokinetics (eye drops)

Trifluridine passes the cornea and is found in the aqueous humour. Systemic absorption is negligible.

Pharmacokinetics (oral)

5-Trifluoromethyl-2,4(1H,3H)-pyrimidinedione (FTY), the main metabolite

Pharmacokinetic data of oral trifluridine have only been evaluated in combination with tipiracil, which significantly affects biotransformation of the former. At least 57% of trifluridine are absorbed from the gut, and highest blood plasma concentrations are reached after two hours in cancer patients. The substance has no tendency to accumulate in the body. Plasma protein binding is over 96%. Trifluridine is metabolised by the enzyme thymidine phosphorylase to 5-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (FTY), and also by glucuronidation. Elimination half-life is 1.4 hours on the first day and increases to 2.1 hours on the twelfth day. It is mainly excreted via the kidneys.

Tipiracil causes C_max (highest blood plasma concentrations) of trifluridine to increase 22-fold, and its area under the curve 37-fold, by inhibiting thymidine phosphorylase.

Chemistry

The substance is a white crystalline powder. It is freely soluble in methanol and acetone; soluble in water, ethanol, 0.01 M hydrochloric acid, and 0.01 M sodium hydroxide; sparingly soluble in isopropyl alcohol and acetonitrile; slightly soluble in diethyl ether; and very slightly soluble in isopropyl ether.

External links

• "[Trifluridine therapy in herpetic in keratitis"] (in ro). Revista Medico-Chirurgicala a Societatii de Medici Si Naturalisti Din Iasi 108 (2): 409–412. 2004. PMID 15688823. https://www.revmedchir.ro/index.php/revmedchir/issue/view/72. 
• "Delivery of trifluridine to human cornea and aqueous using collagen shields". The CLAO Journal 24 (2): 122–124. April 1998. PMID 9571274. 
• "Therapeutic response of herpes simplex virus-induced corneal edema to trifluridine in combination with immunosuppressive agents". Investigative Ophthalmology & Visual Science 32 (9): 2455–2461. August 1991. PMID 1907950. 
• "Trifluridine Ophthalmic Solution, 1%". http://ecatalog.alcon.com/pi/Trifluridine_us_en.pdf.