Tipiracil is a drug used in the treatment of cancer. It is approved for use in form of the combination drug

trifluridine/tipiracil Trifluridine/tipiracil, 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 ha ...

for the treatment of unresectable advanced or recurrent

colorectal cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel m ...

. Tipiracil helps maintain the blood concentration of

trifluridine 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 n ...

by inhibiting the enzyme

thymidine phosphorylase Thymidine phosphorylase () is an enzyme that is encoded by the TYMP (gene), TYMP gene and catalyzes the reaction: :thymidine + phosphate \rightleftharpoons thymine + 2-deoxy-alpha-D-ribose 1-phosphate Thymidine phosphorylase is involved in purin ...

which metabolizes trifluridine.

Adverse effects

Adverse effects were not assessed independently of trifluridine, but only in the combination drug.

Interactions

Only ''

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

'' interaction studies are available. In these, tipiracil was transported by the solute carrier proteins

SLC22A2 Solute carrier family 22 member 2 (also termed ''OCT2'' or ''organic cation transporter-2'') is a protein that in humans is encoded by the ''SLC22A2'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to d ...

and SLC47A1. Drugs that interact with these transporters could influence

blood plasma Blood plasma is a light amber-colored liquid component of blood in which blood cells are absent, but contains proteins and other constituents of whole blood in suspension. It makes up about 55% of the body's total blood volume. It is the intra ...

concentrations of tipiracil.

Pharmacology

Mechanism of action

Tipiracil is a thymidine phosphorylase (TPase) inhibitor and inhibits degradation of trifluridine by inhibiting TPase, thus increasing systemic exposure to trifluridine when tipiracil is given together with trifluridine.

Pharmacokinetics

At least 27% of tipiracil is absorbed from the gut. In cancer patients, highest blood plasma concentrations are reached after three hours. The substance has no tendency to accumulate in the body. The ''

'' protein binding in human plasma is below 8%. Tipiracil is not metabolized by

cytochrome P450 Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...

(CYP) enzymes. To a small extent, it is

hydrolyze Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysis ...

d to 6-hydroxymethyluracil, but the main fraction is excreted in unchanged form in the faeces (50%) and urine (27%). Elimination half-life is 2.1 hours on the first day and then slightly increases to 2.4 hours on the twelfth day. Tipiracil causes C_max (highest blood plasma concentrations) of trifluridine to increase 22-fold, and its

area under the curve In mathematics, an integral assigns numbers to functions in a way that describes displacement, area, volume, and other concepts that arise by combining infinitesimal data. The process of finding integrals is called integration. Along with ...

37-fold.

Chemistry

Tipiracil is used in form of the

hydrochloride In chemistry, a hydrochloride is an acid salt resulting, or regarded as resulting, from the reaction of hydrochloric acid with an organic base (e.g. an amine). An alternative name is chlorhydrate, which comes from French. An archaic alternative na ...

, which is a white crystalline powder. Solubility in water is 5 mg/mL; it is also soluble in 0.01 M hydrochloric acid and 0.01 M sodium hydroxide; slightly soluble in

methanol Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical and the simplest aliphatic alcohol, with the formula C H3 O H (a methyl group linked to a hydroxyl group, often abbreviated as MeOH). It is a ...

; very slightly soluble in

ethanol Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an Alcohol (chemistry), alcohol with the chemical formula . Its formula can be also written as or (an ethyl ...

; and practically insoluble in

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 clas ...

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. As an isopropyl group linked to a hydroxyl group (chemical formula ) it is the simple ...

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

diisopropyl ether Diisopropyl ether is 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 indust ...

, and

diethyl ether Diethyl ether, or simply ether, is an organic compound in the ether class with the formula , sometimes abbreviated as (see Pseudoelement symbols). It is a colourless, highly volatile, sweet-smelling ("ethereal odour"), extremely flammable liq ...

. on Lonsurf.

COVID-19

Tipiracil has been shown to inhibit

SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a ...

Nsp15 and interacts with the

uridine Uridine (symbol U or Urd) is a glycosylated pyrimidine analog containing uracil attached to a ribose ring (or more specifically, a ribofuranose) via a β-N1-glycosidic bond. The analog is one of the five standard nucleosides which make up nuclei ...

binding pocket of the enzyme’s active site using a combination of

crystallography Crystallography is the experimental science of determining the arrangement of atoms in crystalline solids. Crystallography is a fundamental subject in the fields of materials science and solid-state physics (condensed matter physics). The wor ...

, biochemical and whole cell assays. It had previously been suggested in a computational

drug repurposing Drug repositioning (also called drug repurposing) involves the investigation of existing drugs for new therapeutic purposes. Repurposing achievements A number of successes have been achieved, the foremost including sildenafil (Viagra) for ere ...

study as the most promising hit targeting the main SARS-CoV-2 protease.

References

{{Portal bar , Medicine Enzyme inhibitors Pyrimidinediones COVID-19 drug development