Pharmacokinetics of S-1, an oral formulation of ftorafur, oxonic acid and 5-chloro-2,4-dihydroxypyridine (molar ratio 1:0.4:1) in patients with solid tumors

  title={Pharmacokinetics of S-1, an oral formulation of ftorafur, oxonic acid and 5-chloro-2,4-dihydroxypyridine (molar ratio 1:0.4:1) in patients with solid tumors},
  author={Godefridus J. Peters and Paul Noordhuis and Andr{\'e} B.P. van Kuilenburg and Jan H. Schornagel and Helen E. Gall and Sandra Turner and Martha Swart and Daphne Voorn and Albert H. van Gennip and Jantien Wanders and Ulbe Holwerda and Kees Smid and Giuseppe Giaccone and Pierre Fumoleau and Cees J. van Groeningen},
  journal={Cancer Chemotherapy and Pharmacology},
S-1 is an oral formulation of ftorafur (FT), oxonic acid and 5-chloro-2,4-dihydroxypyridine (CDHP) at a molar ratio of 1:0.4:1. FT is a 5-fluorouracil (5-FU) prodrug, CDHP is a dihydropyrimidine dehydrogenase (DPD) inhibitor and oxonic acid is an inhibitor of 5-FU phosphoribosylation in the gastrointestinal mucosa and was included to prevent gastrointestinal toxicity. We determined the pharmacokinetics of S-1 in 28 patients at doses of 25, 35, 40 and 45 mg/m2. The plasma Cmax values of FT, 5-FU… 
The Effect of Food on the Pharmacokinetics of S-1 after Single Oral Administration to Patients with Solid Tumors
Food intake affected only the pharmacokinetics of the S-1 constituent oxonic acid but not of FT, CDHP, and 5FU, and this observation might affect the gastrointestinal toxicity and thus the efficacy of S- 1.
Plasma concentrations of 5-fluorouracil and F-β-alanine following oral administration of S-1, a dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, as compared with protracted venous infusion of 5-fluorouracil
The pharmacokinetics and pharmacodynamics of oral S-1, a dihydropyrimidine dehydrogenase (DPD) inhibitory fluoropyrimidine, were compared with those of protracted venous infusion (PVI) of
A phase I study evaluating the effect of CDHP as a component of S-1 on the pharmacokinetics of 5-fluorouracil.
The DPD inhibitory action of CDHP contributes to a decrease in5-FU catabolism and to significantly higher blood levels of 5-FU compared to FT alone, according to the pharmacokinetic profile of S-1 to that of FT alone.
Pharmacokinetic evaluation of novel oral fluorouracil antitumor drug S-1 in Chinese cancer patients
The newly developed generic formulation and reference formulation of S-1 have similar pharmacokinetics with one dose (40 mg/m2) in Chinese cancer patients and both the formulations are well tolerated.
Formation Pathways of γ-Butyrolactone from the Furan Ring of Tegafur during Its Conversion to 5-Fluorouracil
GBL/GHB is generated from FT through the formation of SA and 4-OH-BTL but not directly from FT, suggesting that GBL/ GHB may be mainly generated through the CYP2A6-mediated form of SA.
A phase II and pharmacokinetic study of first line S-1 for advanced gastric cancer in Taiwan
The efficacy, toxicity and pharmacokinetic profiles of S-1 in current study are compatible with those from other Asian populations, and trend toward lower AUC5–FU, and higher AUCFT and AUCOxo comparing to most Western reports.
S-1 as a core anticancer fluoropyrimidine agent
The alternate-day S-1 administration can reduce the GI toxicities and myelotoxicities of 5-FU without reducing its anticancer efficacy, enabling patients to continue the oral administration for 6 – 12 months.
Current Development of Anti-Cancer Drug S-1.
The present article reviews the current development of clinical study of S-1, a novel oral fluoropyrimidine derivative used for treating gastric, pancreatic, lung, head, neck and breast carcinomas, and is associated with low gastrointestinal toxicity.
5-Fluorouracil derivatives: a patent review
The search for less toxic 5-FU derivatives, which diminish or circumvent some of its disadvantages, has allowed the development of selective antitumor prodrugs and novel methods for tissue-specific drug delivery.
A case of acute toxicosis caused by ts-1® for suicide
A patient with acute toxicosis who orally ingested a large dose of TS-1® 1400 mg in an effort to commit suicide was saved without severe side effects.


Antitumor activity and low intestinal toxicity of S-1, a new formulation of oral tegafur, in experimental tumor models in rats
The results suggest that CDHP, which is a potent inhibitor of 5-FU degradation, increases the antitumor activity of FT, and that Oxo, who is an inhibitor of5-FU phosphorylation, locally protects the gastrointestinal tract from 5-fluorouracil-induced toxicity without decreasing the antitUMor activity.
Pharmacokinetic study of S-1, a novel oral fluorouracil antitumor drug.
  • K. Hirata, N. Horikoshi, T. Shirasaka
  • Medicine, Chemistry
    Clinical cancer research : an official journal of the American Association for Cancer Research
  • 1999
S-1 may improve patients' quality of life because the pharmacokinetics of orally administered S-1 is almost similar to that of continuous i.v. infusion of 5-FU, it is concluded.
5-Fluorouracil concentrations in human plasma following R,S-1-(tetrahydro-2-furanyl)-5-fluorouracil (ftorafur) administration.
Exceedingly low FUra concen trations after therapeutic doses of the prodrug R,S-1-(tetrahydro-2-furanyl)-5-fluorouracil suggest that metabolically gener ated F Ura is further metabolized before redistribution to the systemic circulation.
Comparison of 5-fluorouracil pharmacokinetics in patients receiving continuous 5-fluorouracil infusion and oral uracil plus N1-(2'-tetrahydrofuryl)-5-fluorouracil.
  • D. Ho, R. Pazdur, J. Kuritani
  • Medicine, Biology
    Clinical cancer research : an official journal of the American Association for Cancer Research
  • 1998
Oral UFT would eliminate the incidence of venous thrombosis and catheter-related infections sometimes seen in patients treated with CIFU, and the convenience and decreased cost of oral administration may be preferable for many patients, particularly those receiving 5-FU for palliation.
Phase I clinical and pharmacokinetic study of oral S-1 in patients with advanced solid tumors.
A statistically significant relationship was observed between the severity of diarrhea and pharmacokinetic parameters of 5-FU, and the recommended dose of S-1 in chemotherapy-naive or minimally chemotherapy-exposed patients is 40 mg/m(2) bid on 28 consecutive days, every 5 weeks.
Experimental neurotoxicity of 5-fluorouracil and its derivatives is due to poisoning by the monofluorinated organic metabolites, monofluoroacetic acid and α-fluoroβ-alanine
It was concluded that the subacute and chronic neurotoxicity of FU and its derivatives in dogs and cats is due to intoxication with the monofluorinated organic metabolites, FA and FBAL, and that the direct action of FA andFBAL on myelin and the action of FBAL on energy metabolism or vessels of the mid brain were proposed as the main pathogenetic factor involved.
Effect of food on the pharmacokinetics of capecitabine and its metabolites following oral administration in cancer patients.
It is recommended that capecitabine be administered with food as this procedure was used in the clinical trials, and a profound influence on Cmax of cape citabine and most of its metabolites was found.
Antitumor activity of 1 M tegafur-0.4 M 5-chloro-2,4-dihydroxypyridine-1 M potassium oxonate (S-1) against human colon carcinoma orthotopically implanted into nude rats.
It is suggested that this orthotopic human colorectal tumor model in nude rats is useful to evaluate the clinical therapeutic efficacy of drugs or therapies for coloretectal cancer, and that S-1 had a higher therapeutic effect on human colorescent tumor than UFT did.
Inhibition by oxonic acid of gastrointestinal toxicity of 5-fluorouracil without loss of its antitumor activity in rats.
It is suggested that coadministration of oxonic acid suppresses the GI toxicity of 5-FU and its derivatives without affecting their antitumor activity and thus prolongs the life span of cancer-bearing rats.