Trifluridine

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Trifluridine
Trifluridine structure.svg
Clinical data
Trade names Viroptic; Lonsurf (+tipiracil)
Other namesα,α,α-trifluorothymidine; 5-trifluromethyl-2′-deoxyuridine; FTD5-trifluoro-2′-deoxythymidine; TFT; CF3dUrd; FTD; F3TDR; F3Thd
AHFS/Drugs.com Monograph
License data
Routes of
administration
Eye drops; tablets (+tipiracil)
ATC code
Legal status
Legal status
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
  • 1-[4-Hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-(trifluoromethyl)-(1H,3H)-pyrimidine-2,4-dione
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.657 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C10H11F3N2O5
Molar mass 296.202 g·mol−1
3D model (JSmol)
  • FC(F)(F)C=1C(=O)NC(=O)N(C=1)[C@@H]2O[C@@H]([C@@H](O)C2)CO
  • 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 Yes check.svgY
  • Key:VSQQQLOSPVPRAZ-RRKCRQDMSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Trifluridine (also called trifluorothymidine; abbreviation TFT or FTD [1] ) 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.

Contents

Trifluridine was approved for medical use in 1980. [2] 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. [3]

A Cochrane Systematic Review showed that trifluridine and aciclovir were a more effective treatment than idoxuridine or vidarabine, [4] significantly increasing the relative number of successfully healed eyes in one to two weeks. [4]

For cancer treatment, the combination trifluridine/tipiracil is used.[ citation needed ]

Adverse effects

Common side effects of trifluridine eye drops include transient burning, stinging, local irritation, and edema of the eyelids. [3]

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

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. [5]

For the eye drops, trifluridine absorption is negligible, [3] 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.[ citation needed ]

Pharmacokinetics (eye drops)

Trifluridine passes the cornea and is found in the aqueous humour. Systemic absorption is negligible. [3]

Pharmacokinetics (oral)

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

Tipiracil causes Cmax (highest blood plasma concentrations) of trifluridine to increase 22-fold, and its area under the curve 37-fold, by inhibiting thymidine phosphorylase. [5]

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. [6]

Related Research Articles

<span class="mw-page-title-main">Keratitis</span> Medical condition

Keratitis is a condition in which the eye's cornea, the clear dome on the front surface of the eye, becomes inflamed. The condition is often marked by moderate to intense pain and usually involves any of the following symptoms: pain, impaired eyesight, photophobia, red eye and a 'gritty' sensation.

<span class="mw-page-title-main">Aciclovir</span> Antiviral medication used against herpes, chickenpox and shingles

Aciclovir (ACV), 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 prevention of cytomegalovirus infections following transplant and severe complications of Epstein–Barr virus infection. It can be taken by mouth, applied as a cream, or injected.

<span class="mw-page-title-main">Valaciclovir</span> Anti-herpes virus drug

Valaciclovir, also spelled valacyclovir, is an antiviral medication used to treat outbreaks of herpes simplex or herpes zoster (shingles). It is also used to prevent cytomegalovirus following a kidney transplant in high risk cases. It is taken by mouth.

<span class="mw-page-title-main">Thymidine kinase</span> Enzyme found in most living cells

Thymidine kinase is an enzyme, a phosphotransferase : 2'-deoxythymidine kinase, ATP-thymidine 5'-phosphotransferase, EC 2.7.1.21. It can be found in most living cells. It is present in two forms in mammalian cells, TK1 and TK2. Certain viruses also have genetic information for expression of viral thymidine kinases. Thymidine kinase catalyzes the reaction:

<span class="mw-page-title-main">Vidarabine</span> Chemical compound

Vidarabine or 9-β-D-arabinofuranosyladenine (ara-A) is an antiviral drug which is active against herpes simplex and varicella zoster viruses.

<span class="mw-page-title-main">Ganciclovir</span> Chemical compound

Ganciclovir, sold under the brand name Cytovene among others, is an antiviral medication used to treat cytomegalovirus (CMV) infections.

<span class="mw-page-title-main">Nucleoside analogue</span> Biochemical compound

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 of compounds can deviate from what they mimick in a number of ways, as changes can be made to any of the constituent parts. They are related to nucleic acid analogues.

<span class="mw-page-title-main">Brivudine</span> Chemical compound

Brivudine is an antiviral drug used in the treatment of herpes zoster ("shingles"). Like other antivirals, it acts by inhibiting replication of the target virus.

<span class="mw-page-title-main">Idoxuridine</span> Chemical compound

Idoxuridine is an anti-herpesvirus antiviral drug.

<span class="mw-page-title-main">Corneal ulcer</span> Medical condition of the eye

Corneal ulcer, also called keratitis, is an inflammatory or, more seriously, infective condition of the cornea involving disruption of its epithelial layer with involvement of the corneal stroma. It is a common condition in humans particularly in the tropics and in farming. In developing countries, children afflicted by vitamin A deficiency are at high risk for corneal ulcer and may become blind in both eyes persisting throughout life. In ophthalmology, a corneal ulcer usually refers to having an infection, while the term corneal abrasion refers more to a scratch injury.

<span class="mw-page-title-main">Sorivudine</span> Chemical compound

Sorivudine (INN), is a nucleoside analogue antiviral drug, marketed under trade names such as Usevir and Brovavir (BMS). It is used for the treatment of varicella zoster virus infections.

<span class="mw-page-title-main">Thymidine kinase from herpesvirus</span>

Thymidine kinase from herpesvirus is a sub-family of thymidine kinases that catalyses the transfer of phospho group of ATP to thymidine to generate thymidine monophosphate, which serves as a substrate during viral DNA replication.

<span class="mw-page-title-main">Herpes</span> Viral disease caused by herpes simplex viruses

Herpes simplex, often known simply as herpes, is a viral infection caused by the herpes simplex virus. Herpes infections are categorized by the area of the body that is infected. The two major types of herpes are oral herpes and genital herpes, though other forms also exist.

<span class="mw-page-title-main">Cold sore</span> Herpes simplex virus infection of the lip

A cold sore is a type of herpes infection caused by the herpes simplex virus that affects primarily the lip. Symptoms typically include a burning pain followed by small blisters or sores. The first attack may also be accompanied by fever, sore throat, and enlarged lymph nodes. The rash usually heals within ten days, but the virus remains dormant in the trigeminal ganglion. The virus may periodically reactivate to create another outbreak of sores in the mouth or lip.

<span class="mw-page-title-main">Edoxudine</span> Chemical compound

Edoxudine is an antiviral drug. It is an analog of thymidine, a nucleoside.

<span class="mw-page-title-main">Herpes simplex keratitis</span> Medical condition

Herpetic simplex keratitis is a form of keratitis caused by recurrent herpes simplex virus (HSV) infection in the cornea.

<span class="mw-page-title-main">Trifluridine/tipiracil</span> Combination medication

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 therapeutics have failed. It is a combination of two active pharmaceutical ingredients: trifluridine, a nucleoside analog, and tipiracil, a thymidine phosphorylase inhibitor. Tipiracil prevents rapid metabolism of trifluridine, increasing the bioavailability of trifluridine.

<span class="mw-page-title-main">Tipiracil</span> Chemical compound

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.

<span class="mw-page-title-main">Herpes zoster ophthalmicus</span> Shingles in the human eye

Herpes zoster ophthalmicus (HZO), also known as ophthalmic zoster, is shingles involving the eye or the surrounding area. Common signs include a rash of the forehead with swelling of the eyelid. There may also be eye pain and redness, inflammation of the conjunctiva, cornea or uvea, and sensitivity to light. Fever and tingling of the skin and allodynia near the eye may precede the rash. Complications may include visual impairment, increased pressure within the eye, chronic pain, and stroke.

<span class="mw-page-title-main">Carbocyclic nucleoside</span> Class of chemical compounds

Carbocyclic nucleosides are nucleoside analogues in which a methylene group has replaced the oxygen atom of the furanose ring. These analogues have the nucleobase attached at a simple alkyl carbon rather than being part of a hemiaminal ether linkage. As a result, they have increased chemical stability. They also have increased metabolic stability because they are unaffected by phosphorylases and hydrolases that cleave the glycosidic bond between the nucleobase and furanose ring of nucleosides. They retain many of the biological properties of the original nucleosides with respect to recognition by various enzymes and receptors.

References

  1. Patel AK, Abhyankar R, Brais LK, Duh MS, Barghout VE, Huynh L, et al. (December 2021). "Trifluridine/Tipiracil and Regorafenib in Patients with Metastatic Colorectal Cancer: A Retrospective Study at a Tertiary Oncology Center". The Oncologist. 26 (12): e2161–e2169. doi: 10.1002/onco.13942 . PMC   8649060 . PMID   34406678.
  2. Kimberlin DW (2012). "Antiviral Agents". In Long SS, Pickering LK, Prober CG (eds.). Principles and Practice of Pediatric Infectious Disease. Elsevier Health Sciences. p. 1502. ISBN   978-1437727029.
  3. 1 2 3 4 "Trifluridine". Drugs.com.
  4. 1 2 Wilhelmus KR (January 2015). "Antiviral treatment and other therapeutic interventions for herpes simplex virus epithelial keratitis". The Cochrane Database of Systematic Reviews. 1 (1): CD002898. doi:10.1002/14651858.CD002898.pub5. PMC   4443501 . PMID   25879115.
  5. 1 2 3 Haberfeld H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
  6. "Lonsurf Prescribing Information". Drugs.com.