Determination of S-1 (combined drug of tegafur, 5-chloro-2,4- dihydroxypyridine and potassium oxonate and 5-fluorouracil in human plasma and urine using high-performance liquid chromatography and gas chromatography-negative ion chemical ionization mass spectrometry

Matsushima, Eiji; Yoshida, Kozo; Kitamura, Reiko; Yoshida, Keisuke

doi:10.1016/s0378-4347(96)00429-x

Cited by 81 publications

(69 citation statements)

References 10 publications

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“…Analyses of FT, 5-FU, CDHP, and Oxo were conducted according to the method described by Matsushima et al [20,21]. Briefly, FT was extracted with dichloromethane from each sample and analyzed using HPLC equipped with a UV absorption spectrophotometer.…”

Section: Pharmacokinetic Studymentioning

confidence: 99%

Multi-Institutional Phase II Study of S-1 Monotherapy in Advanced Gastric Cancer with Pharmacokinetic and Pharmacogenomic Evaluations

et al. 2007

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This study describes the first phase II study of S-1, a novel oral fluoropyrimidine, in a non-Japanese Asian population with advanced gastric cancer. S-1 was administered twice daily for 28 days every 6 weeks. A pharmacokinetic study was performed on day 28 of cycles 1 and 3. Genomic DNA from peripheral mononuclear cells was analyzed using a cDNA microarraybased comparative genomic hybridization (CGH) method. Thirty-one patients were initially given a dose of 35 mg/m 2 twice daily (bid) (group 1); then, the protocol was amended by increasing the dose to 40 mg/m 2 bid for an additional 31 patients (group 2) because of good tolerability to S-1. The overall response rate was 19.3% (95% confidence interval, 9.2%-29.5%). Over a median follow-up duration of 265 days, the median time to progression and overall survival time were 126 and 264 days, respectively. The 1-year survival rate was 34%. There was no grade 4 toxicity and the major adverse event was anemia. Pharmacokinetic parameters were similar to those of the previous Japanese reports. Microarray CGH identified 18 genes with copy number changes that were associated with hemoglobin reduction with S-1 treatment. A logistic regression analysis, integrating one clinical parameter (initial hemoglobin level) combined with three genetic copy number variations (HIST1H2BL, C10orf127, and XPNPEP2), provided a predictive model for the development of severe hemoglobin reduction. In conclusion, this study showed the feasibility of using S-1 at 35 mg/m 2 bid in gastric cancer. We suggest that the pharmacogenomic markers identified in this study may be potential candidates for predicting anemia after S-1 treatment. The Oncologist 2007;12:543-554

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Section: Pharmacokinetic Studymentioning

confidence: 99%

Multi-Institutional Phase II Study of S-1 Monotherapy in Advanced Gastric Cancer with Pharmacokinetic and Pharmacogenomic Evaluations

et al. 2007

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“…Analysis of FT, 5-FU, CDHP, and Oxo was conducted according to the method of Matsushima et al [8]. In brief, FT was extracted with dichloromethane from each sample and analyzed using HPLC equipped with a UV absorption spectrometer.…”

Section: Drug Assaymentioning

confidence: 99%

Effect of gastrectomy on the pharmacokinetics of S-1, an oral fluoropyrimidine, in resectable gastric cancer patients

Kochi

Fujii

Kanamori

et al. 2007

Cancer Chemother Pharmacol

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Purpose The eVect of gastrectomy on pharmacokinetics after S-1 administration was investigated. Patients and methods A dose of 40 mg/m 2 of S-1 was administered orally twice daily for 7 days (80 mg/m 2 / day) preoperatively in ten patients with resectable gastric cancer, and the same dose of S-1 was administered for 28 consecutive days after gastrectomy. Plasma concentrations of tegafur, gimeracil, and oteracil potassium, all the components of S-1, and 5-FU were measured on pre-and postoperative days. Concentrations of 5-FU in tumor and normal tissues were also determined. Results At day 4 from the initial preoperative administration of S-1, the AUC of 5-FU was 1,055 § 304 ng h/ ml. At day 18, day 28, and day 42 after gastrectomy, it was 1,012 § 331, 1,070 § 403, and 946 § 226 ng h/ml, respectively. No signiWcant diVerences for plasma 5-FU were observed between pre-and postoperative days. In the resected tumor tissues, concentrations of 5-FU were 242 § 83 ng/g around 4.5 h and 91.7 § 37.0 ng/g around 20 h after the Wnal administration, respectively. Conclusion Gastrectomy does not aVect on pharmacokinetics of 5-FU derived from S-1 regardless of partial or total gastrectomy, indicating that S-1 can be a useful drug in postoperative adjuvant chemotherapy for gastric cancer.

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“…Analysis of 5-FU and uracil was carried out as described by Matsushima et al (1997), with minor modification. 5-Fluorouracil and uracil were extracted with ethyl acetate after washing with dichloromethane and were subjected to a reaction to induce their trimethylsilyl derivatives.…”

Section: Assay Of 5-fu Uracil and Fbalmentioning

confidence: 99%

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

et al. 2003

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The pharmacokinetics and pharmacodynamics of oral S-1, a dihydropyrimidine dehydrogenase (DPD) inhibitory fluoropyrimidine, were compared with those of protracted venous infusion (PVI) of 5-fluorouracil (5-FU). In all, 10 patients with gastric cancer received PVI of 5-FU at a dose of 250 mg m À2 day À1 for 5 days. After a washout period of 9 days, the patients received two divided doses daily for 28 days. S-1 was administered orally at about 0900 and 1900 hours. The daily dose of S-1 in terms of tegafur was 80 mg day À1 in patients with a body surface area (BSA) of o1.25 m 2 , 100 mg day À1 in those with a BSA of X1.25 m 2 to o1.5 m 2 , and 120 mg day Continuous protracted intravenous infusion (PVI) of 5-fluorouracil (5-FU) has a higher response rate, less frequent haematologic toxicity (mainly neutropenia), and more frequent hand -foot syndrome (HFS) than bolus injection of 5-FU in patients with metastatic colorectal cancer (The Meta-Analysis Group in Cancer, 1998). Hand -foot syndrome and stomatitis each occur in about 23% of patients given 5-FU by PVI, whereas grade 3 leukopenia develops in only 1%. Most patients who receive 5-FU by PVI have no severe toxicity; the dose-limiting toxicity (DLT) is HFS (Lokich et al, 1989). Previous clinical trials have shown that PVI of 5-FU is one of the most effective and safest regimens. However, PVI requires a central venous catheter as well as an ambulatory pump, which is expensive and may lead to complications, and adversely affect patients' quality of life. Oral fluoropyrimidine derivatives have been developed to circumvent the problems associated with PVI of 5-FU. S-1 is one such derivative that combines tegafur with two modulators of 5-FU metabolism, 5-chloro-2,4-dihydroxypyridine (CDHP), a reversible inhibitor of dihydropyrimidine dehydrogenase (DPD), and potassium oxonate, in a molar ratio of 1 : 0.4 : 1. Tegafur, an oral prodrug of 5-FU, is gradually converted to 5-FU and rapidly metabolised by DPD in the liver. The DPD-inhibitory activity of CDHP is 180-fold higher than that of uracil, confirmed to be an effective DPD inhibitor in the form of uracil/tegafur (UFT) in vitro. Potassium oxonate is an orotate phosphoribosyl transferase inhibitor that is distributed primarily to the gastrointestinal tract. This component of S-1 decreases the incorporation of 5-fluorouridine triphosphate into RNA in the gastrointestinal mucosa and reduces the incidence of diarrhoea.F-b-alanine (FBAL) is a main metabolite of 5-FU. F-b-alanine and fluorocitrate are thought to cause the cardiotoxic and neurotoxic effects of 5-FU by inhibiting the tricarboxylic acid cycle (Koenig and Patel, 1970;Okeda et al, 1990;Robben et al, 1993;Diasio, 1998;Kuwata et al, 2000;Kato et al, 2001). The CDHP component of S-1 inhibits DPD, the rate-limiting enzyme in the catabolic pathway of 5-FU. Consequently, the plasma FBAL concentration after oral administration of S-1 is significantly lower than that after PVI of 5-FU. However, information on plasma FBAL concentrations in patients given 5-FU remains scant...

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Determination of S-1 (combined drug of tegafur, 5-chloro-2,4- dihydroxypyridine and potassium oxonate and 5-fluorouracil in human plasma and urine using high-performance liquid chromatography and gas chromatography-negative ion chemical ionization mass spectrometry

Cited by 81 publications

References 10 publications

Multi-Institutional Phase II Study of S-1 Monotherapy in Advanced Gastric Cancer with Pharmacokinetic and Pharmacogenomic Evaluations

Multi-Institutional Phase II Study of S-1 Monotherapy in Advanced Gastric Cancer with Pharmacokinetic and Pharmacogenomic Evaluations

Effect of gastrectomy on the pharmacokinetics of S-1, an oral fluoropyrimidine, in resectable gastric cancer patients

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

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