Trifluridine (also called trifluorothymidine; abbreviation TFT or FTD) is an anti-

herpesvirus ''Orthoherpesviridae'', previously named and more widely known as ''Herpesviridae'', is a large family of DNA viruses that cause infections and certain diseases in animals, including humans. The members of this family are commonly known as herp ...

antiviral drug Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Antiviral drugs are a class of antimicrobials ...

, used primarily as prescription

eyedrops Eye drops or eyedrops are liquid drops applied directly to the surface of the eye usually in small amounts such as a single drop or a few drops. Eye drops usually contain saline to match the salinity of the eye. Drops containing only saline ...

. It was sold under the trade name Viroptic by Glaxo Wellcome, now merged into

GlaxoSmithKline GSK plc (an acronym from its former name GlaxoSmithKline plc) is a British Multinational corporation, multinational Pharmaceutics, pharmaceutical and biotechnology company with headquarters in London. It was established in 2000 by a Mergers an ...

. The brand is now wholly owned by

King Pharmaceuticals King Pharmaceuticals, Inc. is a pharmaceutical company, a wholly owned subsidiary of Pfizer based in Bristol, Tennessee. Before being acquired by Pfizer, it was the world's 39th largest pharmaceutical company. On October 12, 2010, King was acqui ...

. Trifluridine was approved for medical use in 1980. It is also a component of the anti-cancer drug

trifluridine/tipiracil Trifluridine/tipiracil (FTD–TPI), sold under the brand name Lonsurf, is a fixed-dose combination medication that is used as a third- or fourth-line treatment of metastatic colorectal cancer or gastric cancer, after chemotherapy and targeted t ...

, which is taken by mouth.

Medical uses

Trifluridine eye drops are used for the treatment of

keratitis Keratitis is a condition in which the human eye, eye's cornea, the clear dome on the front surface of the eye, becomes inflammation, inflamed. The condition is often marked by moderate to intense pain and usually involves any of the following sy ...

and

keratoconjunctivitis Keratoconjunctivitis is a term used to describe inflammation of both the cornea (the clear, front part of the eye) and the conjunctiva (the thin, transparent membrane covering the white part of the eye and lining the inside of the eyelids). This co ...

caused by the

herpes simplex virus Herpes simplex virus 1 and 2 (HSV-1 and HSV-2) are two members of the Herpesviridae#Human herpesvirus types, human ''Herpesviridae'' family, a set of viruses that produce Viral disease, viral infections in the majority of humans. Both HSV-1 a ...

types 1 and 2, as well as for prevention and treatment of

vaccinia virus The vaccinia virus (VACV or VV) is a large, complex, enveloped virus belonging to the poxvirus family. It has a linear, double-stranded DNA genome approximately 190 kbp in length, which encodes approximately 250 genes. The dimensions of the ...

infections of the eye. A Cochrane Systematic Review showed that trifluridine and

aciclovir Aciclovir, also known as acyclovir, is an antiviral medication. It is primarily used for the treatment of herpes simplex virus infections, chickenpox, and shingles. Other uses include the prevention of cytomegalovirus infections following tran ...

were a more effective treatment than idoxuridine or vidarabine, significantly increasing the relative number of successfully healed eyes in one to two weeks.

Adverse effects

Common side effects of trifluridine eye drops include transient burning, stinging, local irritation, and

edema Edema (American English), also spelled oedema (British English), and also known as fluid retention, swelling, dropsy and hydropsy, is the build-up of fluid in the body's tissue (biology), tissue. Most commonly, the legs or arms are affected. S ...

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 ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

'' 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 Blood plasma is a light Amber (color), amber-colored liquid component of blood in which blood cells are absent, but which contains Blood protein, proteins and other constituents of whole blood in Suspension (chemistry), suspension. It makes up ...

concentrations of trifluridine. Being a thymidine phosphorylase inhibitor, trifluridine could also interact with substrates of this enzyme such as

zidovudine Zidovudine (ZDV), also known as azidothymidine (AZT), was the first antiretroviral medication used to prevent and treat HIV/AIDS. It is generally recommended for use in combination with other antiretrovirals. It may be used to prevent mothe ...

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

Pharmacology

Mechanism of action (eye drops)

It is a

nucleoside analogue Nucleoside analogues are structural analogues of a nucleoside, which normally contain a nucleobase and a sugar. Nucleotide analogues are analogues of a nucleotide, which normally has one to three phosphates linked to a nucleoside. Both types ...

, a modified form of

deoxyuridine Deoxyuridine (dU) is a compound and a nucleoside. It belongs to a class of compounds known as Pyrimidine 2'-deoxyribonucleosides and closely resembles the chemical composition of uridine but without the presence of the 2' hydroxyl group. Idoxurid ...

, similar enough to be incorporated into viral

DNA replication In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all life, living organisms, acting as the most essential part of heredity, biolog ...

, but the –CF₃ group added to the

uracil Uracil () (nucleoside#List of nucleosides and corresponding nucleobases, symbol U or Ura) is one of the four nucleotide bases in the nucleic acid RNA. The others are adenine (A), cytosine (C), and guanine (G). In RNA, uracil binds to adenine via ...

component blocks

base pair A base pair (bp) is a fundamental unit of double-stranded nucleic acids consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both DNA ...

ing, thus interfering with viral DNA replication.

Pharmacokinetics (eye drops)

Trifluridine passes the

cornea The cornea is the transparency (optics), transparent front part of the eyeball which covers the Iris (anatomy), iris, pupil, and Anterior chamber of eyeball, anterior chamber. Along with the anterior chamber and Lens (anatomy), lens, the cornea ...

and is found in the

aqueous humour The aqueous humour is a transparent water-like fluid similar to blood plasma, but containing low protein concentrations. It is secreted from the ciliary body, a structure supporting the lens of the eyeball. It fills both the anterior and the po ...

. Systemic absorption is negligible.

Pharmacokinetics (oral)

Pharmacokinetic data of oral trifluridine have only been evaluated in combination with

tipiracil Tipiracil is a drug used in the treatment of cancer. It is approved for use in form of the combination drug trifluridine/tipiracil for the treatment of unresectable advanced or recurrent colorectal cancer. Tipiracil helps maintain the blood con ...

, which significantly affects

biotransformation Biotransformation is the biochemical modification of one chemical compound or a mixture of chemical compounds. Biotransformations can be conducted with whole cells, their lysates, or purified enzymes. Increasingly, biotransformations are effected ...

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(1''H'',3''H'')-pyrimidinedione (FTY), and also by

glucuronidation Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve gly ...

. 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 In mathematics, an integral is the continuous analog of a sum, which is used to calculate areas, volumes, and their generalizations. Integration, the process of computing an integral, is one of the two fundamental operations of calculus,Inte ...

37-fold, by inhibiting thymidine phosphorylase.

Chemistry

The substance is a white crystalline powder. It is freely soluble in

methanol Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical compound and the simplest aliphatic Alcohol (chemistry), alcohol, with the chemical formula (a methyl group linked to a hydroxyl group, often ab ...

and

acetone Acetone (2-propanone or dimethyl ketone) is an organic compound with the chemical formula, formula . It is the simplest and smallest ketone (). It is a colorless, highly Volatile organic compound, volatile, and flammable liquid with a charact ...

; soluble in water,

ethanol Ethanol (also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound with the chemical formula . It is an Alcohol (chemistry), alcohol, with its formula also written as , or EtOH, where Et is the ps ...

, 0.01 M

hydrochloric acid Hydrochloric acid, also known as muriatic acid or spirits of salt, is an aqueous solution of hydrogen chloride (HCl). It is a colorless solution with a distinctive pungency, pungent smell. It is classified as a acid strength, strong acid. It is ...

, and 0.01 M sodium hydroxide; sparingly soluble in

isopropyl alcohol Isopropyl alcohol (IUPAC name propan-2-ol and also called isopropanol or 2-propanol) is a colorless, flammable, organic compound with a pungent alcoholic odor. Isopropyl alcohol, an organic polar molecule, is miscible in water, ethanol, an ...

and

acetonitrile Acetonitrile, often abbreviated MeCN (methyl cyanide), is the chemical compound with the formula and structure . This colourless liquid is the simplest organic nitrile (hydrogen cyanide is a simpler nitrile, but the cyanide anion is not class ...

; slightly soluble in

diethyl ether Diethyl ether, or simply ether, is an organic compound with the chemical formula , sometimes abbreviated as . It is a colourless, highly Volatility (chemistry), volatile, sweet-smelling ("ethereal odour"), extremely flammable liquid. It belongs ...

; and very slightly soluble in

isopropyl ether Diisopropyl ether is a secondary ether that is used as a solvent. It is a colorless liquid that is slightly soluble in water, but miscible with organic solvents. It is used as an extractant and an oxygenate gasoline additive. It is obtained indus ...

References

External links

* * * * {{Ophthalmological anti-infectives Anti-herpes virus drugs Antineoplastic drugs Trifluoromethyl compounds Drugs developed by GSK plc Drugs developed by Pfizer Pyrimidinediones