Tipiracil

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Tipiracil
Clinical data
License data
Pharmacokinetic data
Bioavailability≥27%
Protein binding<8%
Metabolism10
Elimination half-life2.1–2.4 hrs
ExcretionFaeces (50%), urine (27%)
Identifiers
  • 5-Chloro-6-[(2-imino-1-pyrrolidinyl)methyl]-2,4(1H,3H)-pyrimidinedione
JSmol)
Solubility in water5 mg/mL (20 °C)
  • C1CC(=N)N(C1)Cc2c(c(=O)[nH]c(=O)[nH]2)Cl
  • InChI=1S/C9H11ClN4O2/c10-7-5(12-9(16)13-8(7)15)4-14-3-1-2-6(14)11/h11H,1-4H2,(H2,12,13,15,16)
  • Key:QQHMKNYGKVVGCZ-UHFFFAOYSA-N

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.[1]

Tipiracil helps maintain the blood concentration of trifluridine by inhibiting the enzyme thymidine phosphorylase which metabolizes trifluridine.[1][2]

Adverse effects

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

Interactions

Only

SLC47A1. Drugs that interact with these transporters could influence blood plasma concentrations of tipiracil.[3]

Pharmacology

Mechanism of action

Further information: Trifluridine/tipiracil § 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.[3]

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

hydrolyzed to 6-hydroxymethyluracil,[dubious – discuss] 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.[3][4]

Tipiracil causes Cmax (highest blood plasma concentrations) of trifluridine to increase 22-fold, and its area under the curve 37-fold.[3]

Chemistry

Tipiracil is used in form of the

M hydrochloric acid and 0.01 M sodium hydroxide; slightly soluble in methanol; very slightly soluble in ethanol; and practically insoluble in acetonitrile, isopropyl alcohol, acetone, diisopropyl ether, and diethyl ether.[6]

COVID-19

Tipiracil has been shown to inhibit SARS-CoV-2 Nsp15 and interacts with the uridine binding pocket of the enzyme's active site using a combination of crystallography, biochemical and whole cell assays.[7] It had previously been suggested in a computational

drug repurposing study as the most promising hit targeting the main SARS-CoV-2 protease.[8]

References

  1. ^ a b "Taiho's Lonsurf(R) (trifluridine and tipiracil hydrochloride) Tablets Approved In Japan for Treatment of Advanced Metastatic Colorectal Cancer" (Press release). March 24, 2014.
  2. PMID 25230742
    .
  3. ^ a b c d e Haberfeld H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
  4. ^ "Lonsurf: EPAR – Product Information" (PDF). European Medicines Agency. 12 May 2016.
  5. ^ "Tipiracil hydrochloride". Sigma Aldrich. Retrieved 28 September 2016.
  6. ^ "Lonsurf Prescribing Information". Drugs.com.
  7. PMID 33564093
    .
  8. PMID 32962867
    .
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