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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/10/16 10:14:00」(JST)

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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,^{[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 C_max (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

^ ^a ^b "Taiho's Lonsurf(R) (trifluridine and tipiracil hydrochloride) Tablets Approved In Japan for Treatment of Advanced Metastatic Colorectal Cancer". March 24, 2014.
^ 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 4240496. PMID 25230742.
^ ^a ^b ^c ^d ^e Haberfeld, H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
^ "Lonsurf: EPAR – Product Information" (PDF). European Medicines Agency. 12 May 2016.
^ "Tipiracil hydrochloride". Sigma Aldrich. Retrieved 28 September 2016.
^ FDA Professional Drug Information on Lonsurf.

UpToDate Contents

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1. 転移性大腸癌に対する全身化学療法：終了した臨床試験 systemic chemotherapy for metastatic colorectal cancer completed clinical trials
2. 手術不能な転移性大腸癌に対する全身化学療法：治療に関する推奨 systemic chemotherapy for nonoperable metastatic colorectal cancer treatment recommendations
3. 高齢患者およびperformance statusのスコアが低い患者における転移性大腸癌に対する治療 therapy for metastatic colorectal cancer in elderly patients and those with a poor performance status
4. 転移性大腸癌に対する全身化学療法：一般原則 systemic chemotherapy for metastatic colorectal cancer general principles
5. フルオロピリミジンによる心毒性：発生率、臨床症状、発生機序、マネージメント fluoropyrimidine associated cardiotoxicity incidence clinical manifestations mechanisms and management

English Journal

TAS-102: a novel antimetabolite for the 21st century.

Uboha N1, Hochster HS2.
Future oncology (London, England).Future Oncol.2015 Nov 30. [Epub ahead of print]
TAS-102, a novel antimetabolite combination chemotherapy agent, consists of a rediscovered antimetabolite agent, trifluorothymidine (trifluridine) combined with the metabolic inhibitor of thymidine phosphorylase, tipiracil, in a 1:0.5 molar ratio. Mechanism of action studies suggest that this agent
PMID 26616466

TAS-102, a novel antitumor agent: A review of the mechanism of action.

Lenz HJ1, Stintzing S2, Loupakis F3.
Cancer treatment reviews.Cancer Treat Rev.2015 Nov;41(9):777-83. doi: 10.1016/j.ctrv.2015.06.001. Epub 2015 Jun 6.
Inhibition of nucleoside metabolism is an important principle in cancer therapy as evidenced by the role of fluoropyrimidines, such as 5-fluorouracil (5-FU), and antifolates in the treatment of many cancers. TAS-102 is an oral combination therapy consisting of trifluridine (FTD), a thymidine-based n
PMID 26428513

TAS-102 for the treatment of metastatic colorectal cancer.

Salvatore L1,2, Rossini D1,2, Moretto R1,2, Cremolini C1,2, Schirripa M1,2, Antoniotti C1,2, Marmorino F1,2, Loupakis F1,2, Falcone A1,2, Masi G1,2.
Expert review of anticancer therapy.Expert Rev Anticancer Ther.2015 Nov;15(11):1283-92. doi: 10.1586/14737140.2015.1105746. Epub 2015 Oct 28.
The survival of patients with metastatic colorectal cancer has notably increased in the past 20 years, from 12 months to around 30 months. Nevertheless, the prognosis of patients pretreated with all available agents is poor and there is high unmet need for newer treatments. TAS-102 is an orally adm
PMID 26509228

Related Pictures

Tipiracil and Trifluridine Are Powerful Trifluridine/tipiracil - Wikipedia Tipiracil - Wikipedia, the free and Tipiracil Mechanism of Action Tipiracil Hydrochloride - Structural Lonsurf (trifluridine and tipiracil) for Tipiracil cancer drug molecule - Stock

★リンクテーブル★

リンク元

「チピラシル」

Tipiracil
Systematic (IUPAC) name
	5-Chloro-6-[(2-imino-1-pyrrolidinyl)methyl]-2,4(1H,3H)-pyrimidinedione
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
ChEMBL	CHEMBL235668
Chemical data
Formula	C9H11ClN4O2
Molar mass	242.67 g/mol
	SMILES C1CC(=N)N(C1)Cc2c(c(=O)[nH]c(=O)[nH]2)Cl ;
	InChI 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 ;
Physical data
Solubility in water	5 mg/mL (20 °C)

　　[★]

英: tipiracil
商: ロンサーフ配合

[prnewswire-1] "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 4240496. PMID 25230742.

[AC-3] 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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tipiracil