Tipiracil

Tipiracil
Pharmacokinetic data
Bioavailability ≥27%
Protein binding <8%
Biological half-life 2.1–2.4 hrs
Excretion Faeces (50%), urine (27%)
Identifiers
CAS Number 183204-74-2
183204-72-0 (HCl)
PubChem (CID) 6323266
DrugBank DB09343
ChemSpider 13243748
KEGG D10467
ChEBI CHEBI:90879 YesY
ChEMBL CHEMBL235668
Chemical and physical data
Formula C9H11ClN4O2
Molar mass 242.67 g/mol
3D model (Jmol) Interactive image
Solubility in water 5 mg/mL (20 °C)

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.

Interactions

Only in vitro interaction studies are available. In these, tipiracil was transported by the solute carrier proteins SLC22A2 and SLC47A1. Drugs that interact with these transporters could influence blood plasma concentrations of tipiracil.[3]

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.[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 accumulate in the body. The in vitro protein binding in human plasma is below 8%. Tipiracil is not metabolized by cytochrome P450 (CYP) enzymes. To a small extent, it is hydrolyzed 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.[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 hydrochloride,[3] which is a white crystalline powder. Solubility in water is 5 mg/mL;[5] it is also soluble in 0.01 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]

References

  1. 1 2 "Taiho's Lonsurf(R) (trifluridine and tipiracil hydrochloride) Tablets Approved In Japan for Treatment of Advanced Metastatic Colorectal Cancer". March 24, 2014.
  2. ↑ Tanaka, N; Sakamoto, K; Okabe, H; Fujioka, A; Yamamura, K; Nakagawa, F; Nagase, H; Yokogawa, T; Oguchi, K; Ishida, K; Osada, A; Kazuno, H; Yamada, Y; Matsuo, K (2014). "Repeated oral dosing of TAS-102 confers high trifluridine incorporation into DNA and sustained antitumor activity in mouse models". Oncology Reports. 32 (6): 2319–26. doi:10.3892/or.2014.3487. PMC 4240496Freely accessible. PMID 25230742.
  3. 1 2 3 4 5 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. ↑ FDA Professional Drug Information on Lonsurf.
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