[Pharmacokinetics of S-1 capsule in patients with advanced gastric cancer].

The study is to investigate the pharmacokinetics of S-1 capsule (tegafur, gimeracil and potassium oxonate capsule) in patients with advanced gastric cancer after single and multiple oral administration. Twelve patients with advanced gastric cancer were recruited to the study. The dose of S-1 for each patient was determined according to his/her body surface area (BSA). The dose for single administration was 60 mg every subject. The dose for multiple administration for one subject was as follows: 100 mg x d(-1) or 120 mg x d(-1), 28-days consecutive oral administration. The pharmacokinetic parameters of tegafur, 5-fluorouracil, gimeracil, potassium oxonate and uracil after single oral administration were as follows: (2,207 +/- 545), (220.0 +/- 68.2), (374.9 +/- 103.0), (110.5 +/- 100.8) and (831.1 +/- 199.9) ng x mL(-1) for Cmax; (11.8 +/- 3.8), (4.4 +/- 3.3), (7.8 +/- 5.1), (3.1 +/- 0.9) and (8.8 +/- 4.1) h for t1/2, respectively. After six days oral administration, the average steady state plasma concentrations (Cav) of tegafur, 5-fluorouracil, gimeracil, potassium oxonate and uracil were (2,425 +/- 1,172), (73.88 +/- 18.88), (162.6 +/- 70.8), (36.89 +/- 29.35) and (435.3 +/- 141.0) ng x mL(-1), respectively, and the degree of fluctuation (DF) were (1.0 +/- 0.2), (2.5 +/- 0.4), (3.1 +/- 0.8), (2.4 +/- 0.8) and (1.5 +/- 0.3), respectively. The cumulative urine excretion percentage of tegafur, 5-fluorouracil, gimeracil and potassium oxonate in urine within 48 h were (4.2 +/- 2.8) %, (4.7 +/- 1.6) %, (18.5 +/- 6.0) % and (1.7 +/- 1.2) %, repectively, after single oral administration of S-1. The results exhibited that tegafur had some drug accumulation observed, and gimeracil, potassium oxonate, 5-fluorouracil and uracil had no drug accumulation observed.

Two dosages of oral fluoropyrimidine S-1 of 35 and 40 mg/m2 bid: comparison of the pharmacokinetic profiles in Korean patients with advanced gastric cancer.

OBJECTIVE: In this study, we compared the pharmacokinetic profiles of 5-fluorouracil (5-FU), tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo) after administration of S-1 at 35 or 40 mg/m(2) bid for 28 consecutive days, in Cycles 1 and 3, in patients with advanced gastric cancer. METHODS: Three patients were enrolled for each dosage. S-1 dosage was assigned based on body surface area (BSA), which is different from the Japanese dosing system. The median daily dose per BSA was 76 mg/m(2), ranging from 70 to 88 mg/m(2). RESULTS: Plasma levels of 5-FU, tegafur, CDHP and Oxo at 4 h post-dose reached steady-state on day 8. The estimated steady-state level was dependent on S-1 dosage. There were no intercyclic differences of pre-dose and 4 h post-dose levels between Cycles 1 and 3, implying no cumulative effect of S-1 was shown probably due to 2-week drug-resting period. Pharmacokinetic profiles on day 28 were similar to previous Japanese report. C(max) and AUC(0-48 h) values of each S-1 component increased depending on S-1 dosage. Pharmacokinetic parameters were not correlated with tumor response or toxicity. CONCLUSIONS: We suggest that these pharmacokinetic profiles of Asian population could provide a basis for schedule optimization and for additional studies on interaction with other antitumor drugs.

Pharmacokinetic and bioequivalence study between two formulations of S-1 in Korean gastric cancer patients.

PURPOSE: S-1 is an oral fluoropyrimidine anticancer drug consisting of the 5-fluorouracil prodrug tegafur combined with gimeracil and oteracil. The purpose of this study was to evaluate the pharmacokinetic (PK), bioequivalence, and safety of a newly developed generic formulation of S-1 compared with the branded reference formulation, in Korean gastric cancer patients. METHODS: This was a single-center, randomized, open-label, single-dose, two-treatment, two-way crossover study. Eligible subjects were randomly assigned in a 1:1 ratio to receive the test formulation or reference formulation, followed by a one-week washout period and administration of the alternate formulation. Serial blood samples were collected at 0 hrs (predose), 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, and 48 hrs after dosing in each period. The plasma concentrations of tegafur, 5-FU, gimeracil, and oteracil were analyzed using a validated liquid chromatography-tandem mass spectrometry method. The PK parameters were calculated using a non-compartmental method. RESULTS: In total, 29 subjects completed the study. All of the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) fell within the predetermined acceptance range. No serious adverse events were reported during the study. CONCLUSION: The new S-1 formulation met the Korean regulatory requirement for bioequivalence. Both S-1 formulations were well tolerated in all subjects.Clinical trial registry: https://cris.nih.go.kr CRIS KCT0003855.

Development of a pharmacokinetic model to optimize the dosage regimen of TS-1, a combination preparation of tegafur, gimeracil and oteracil potassium.

BACKGROUND: TS-1 is a combination preparation of tegafur, a prodrug of 5-fluorouracil (5-FU), with gimeracil, a potent inhibitor of dihydropyrimidine dehydrogenase (DPD), which mediates the inactivation of 5-FU. UFT is a combination preparation of tegafur with uracil, which also inhibits DPD, though less potently; UFT has a higher content of tegafur than that in TS-1. We aimed to develop a pharmacokinetic model to describe the kinetics of tegafur and 5-FU after the administration of TS-1 and UFT. METHODS: We developed a model incorporating the inhibition of DPD by gimeracil and uracil, and fitted the model to the observed kinetics of tegafur and 5-FU after the administration of TS-1 and UFT. Then, we simulated the plasma 5-FU profiles in patients with renal dysfunction and those after replacement of TS-1 with UFT and compared them with the observed profiles. RESULTS: The developed model could appropriately describe the plasma concentration profiles of 5-FU and tegafur after the administration of TS-1 in patients with normal and impaired renal function. CONCLUSION: The developed model may be useful to optimize the dosage regimen of TS-1 under various clinical conditions.

[A phase I study of postoperative combination therapy with TS-1 and low dose cisplatin against stage IV gastric carcinoma].

A dose-escalation study was conducted for postoperative patients with stage IV gastric cancer to determine the recommended dose of daily intravenous cisplatin combined with a fixed dose of TS-1. TS-1 was administered orally twice daily for 2 weeks followed by a 1-week rest. The dose of TS-1 was based on the body surface area (BSA) as follows: 80 mg/day for BSA less than 1.25, 100 mg/day for BSA 1.25 to less than 1.50, and 120 mg/day for BSA 1.5 or more. Three dose levels of cisplatin (2, 4, 6 mg/m(2)) were studied, and two courses were performed. Cisplatin was infused on day 1-5 and 8-12 for 30 minutes. The National Cancer Institute common toxicity criteria (NCI-CTC Version 3) were used to evaluate the grade of toxicity. Three patients enrolled in each level. Dose escalation was performed when dose-limiting toxicities (DLT) were seen in 0/3, and 3 more cases of the same level were added when DLTs were seen 1-2/3. Maximum-tolerated dose (MTD) were determined when DLTs were seen in 3 cases. DLTs were not recorded during the administration of CDDP up to 4 mg/m(2). However, DLTs were seen 3/3 at level 3. From these results, cisplatin of 4 mg/m(2)was determined to be the recommended dose (RD) in this protocol for postoperative stage IV gastric carcinoma.

Pharmacokinetics of S-1 in patients with peritoneal dissemination of gastric cancer.

The response of gastric cancer with peritoneal dissemination to systemic chemotherapy may be negatively affected by poor drug delivery due to the blood-peritoneal barrier. However, S-1 has been reported to be effective. We examined the pharmacokinetics of S-1 in 14 patients who had gastric cancer with peritoneal dissemination. S-1 was given from the morning of the day before surgery to the morning of surgery. Concentrations of 5-fluorouracil (5-FU) and gimeracil (CDHP) were measured in the serum, ascites, disseminated peritoneal nodes, and normal peritoneum. There was a strong correlation between 5-FU and CDHP concentrations in peritoneal tissues. The concentrations of 5-FU and CDHP in the serum were similar to those in ascites. The concentration of 5-FU was significantly higher in disseminated nodes than in the normal peritoneum. After administration of S-1 to gastric cancer patients with peritoneal dissemination, 5-FU and CDHP in the serum linearly pass through the peritoneum and enter the ascites. High concentrations of 5-FU selectively penetrate disseminated peritoneal cells.

Pharmacokinetic study of S-1, a novel oral fluorouracil antitumor drug.

S-1 is a novel oral fluorouracil antitumor drug that combines three pharmacological agents: tegafur (FT), which is a prodrug of 5-fluorouracil (5-FU); 5-chloro-2,4-dihydroxypyridine (CDHP), which inhibits dihydropyrimidine dehydrogenase (DPD) activity; and potassium oxonate (Oxo), which reduces gastrointestinal toxicity. Phase I and early Phase II clinical trials have already been completed. On the basis of the results of these trials, 80 mg/m2/day, given daily in two divided doses after breakfast and supper, a 28-day consecutive oral regimen is recommended. In this study, we investigated the pharmacokinetics of 5-FU, intact FT, CDHP, and Oxo, after administration of S-1, at a standard dose of 80 mg/m2/day, in advanced cancer patients. Twelve patients were recruited to the study; 5 patients with gastric cancer, 4 with colorectal cancer, and 3 with breast cancer. Among them, analysis was conducted on 12 patients for single administration and on 10 patients for consecutive administration. The initial dose of S-1 for each patient was determined according to his/her body surface area (BSA) as follows: for BSA < 1.25 m2, 80 mg/body/day; for 1.25 m2 < or = BSA < 1.5 m2, 100 mg/day; and for 1.5 m2 < or = BSA, 120 mg/day. For single administration, half of the standard dose was used. For 28-day consecutive administration, the standard dose was given daily in two divided doses. The average single dose per BSA was 35.9 mg/m2 (31.7-39.7 mg/m2). Pharmacokinetic parameters of plasma 5-FU were as follows: Cmax, 128.5 +/- 41.5 ng/ml; Tmax, 3.5 +/- 1.7 h; AUC(0-14), 723.9 +/- 272.7 ng x h/ml; and T(1/2), 1.9 +/- 0.4 h. In the 28-day consecutive regimen, there were no fluctuations in pharmacokinetics nor any drug accumulation. Because the pharmacokinetics of orally administered S-1 is almost similar to that of continuous i.v. infusion of 5-FU, we concluded that S-1 may improve patients' quality of life.

[TS-1 treatment for progressive gastric cancer in a patient on chronic dialysis--assessment of dosage regimen by monitoring blood concentrations of therapeutic drugs (TDM)].

The optimum dose of TS-1 for the treatment of peritoneally disseminated gastric cancer in a patient with chronic renal failure undergoing chronic dialysis was estimated by monitoring the blood concentrations of 5-FU and gimeracil (CDHP) [therapeutic drug monitoring (TDM)] during administration of TS-1. Immediately after dialysis, 50 mg or 40 mg of TS-1, corresponding to 50% and 40% of the standard dose (100mg for this patient), respectively, was administered orally once a day every other day, and TDM was conducted. Compared with the pharmacokinetic parameters of 5-FU at the time of the initial administration of 50 mg or 40 mg of TS-1 and that of cancer patients with normal renal function, the AUC shown in the administration of 40 mg was equivalent to that observed with a single safe dose of 100 mg in patients with normal renal function. Based on this observation, the daily TS-1 dose was set at 40 mg in this patient, and TS-1 treatment was started after confirming the absence of the accumulation of 5-FU or CDHP during repeated administrations. In this treatment protocol, TS-1 was administered 11 times at a daily dose of 40 mg every other day immediately after dialysis, followed by a rest. This .administration schedule was defined as one course. Under these conditions, the patient was treated on an outpatient basis, and the treatment could be safely continued without the development of any severe adverse events, such as myelosuppression.

Postgastrectomy pharmacokinetic changes of S-1 in patients with localized advanced gastric cancer.

S-1 is an oral 5-fluorouracil agent containing tegafur, 5-chloro-2, 4-dihydroxypyridine (CDHP), and potassium oxonate. This study explored the pharmacokinetics of S-1 and pharmacokinetic changes after gastric surgery in patients with resectable gastric cancer who received pre- and postoperative S-1 plus docetaxel. Serial blood was drawn before and after gastrectomy from 37 patients for pharmacokinetic analysis. The pharmacokinetics of tegafur, 5-fluorouracil, and CDHP were analyzed by noncompartmental analysis (NCA) methods and by modeling. In modeling analysis, CHDP concentrations were incorporated in the model as a time-varying covariate that inhibits the clearance of 5-fluorouracil following an inhibitory Emax model. In NCA, the pharmacokinetics of tegafur and 5-FU before and after gastric surgery were similar, although average maximum concentrations of 5-FU were decreased with statistical significance after gastrectomy. Median Tmax of tegafur was shorter after surgery without statistical significance. In modeling analysis, tegafur was best fitted by mixed zero and first-order absorption. The only difference in the final pharmacokinetic model around gastrectomy was the presence of an absorption lag of 0.23 hours before surgery. Incorporation of CDHP concentrations significantly improved the model. Although some pharmacokinetic results showed statistically significant changes after gastrectomy, these differences seem to be too small to have any clinical implication.

A novel mutant allele of the CYP2A6 gene (CYP2A6*11 ) found in a cancer patient who showed poor metabolic phenotype towards tegafur.

In a clinical study, a newly developed anticancer drug, TS-1 capsule, which contained tegafur (FT) and 5-chloro-2,4-dihydroxypyridine, an inhibitor of dihydropyrimidine dehydrogenase, was orally administered to five gastric cancer patients (patients 1-5). The total area under the plasma FT concentration-time curve in patient 1 was four-fold higher than in other patients. Since cytochrome P450 2A6 (CYP2A6) has been reported to metabolize FT to yield 5-fluorouracil (5-FU), it was postulated that the poor metabolic phenotype of patient 1 was caused by mutations of the CYP2A6 gene. Thus, alleles for the CYP2A6 genes derived from patient 1 were completely sequenced. It was found that one allele was CYP2A6*4C, which was a whole deleted allele for the human CYP2A6 gene. The other allele was a novel mutant allele (CYP2A6*11) in which thymine at nucleotide 670 was changed to cytosine. The nucleotide change caused an amino acid change from serine at residue 224 to proline. To examine whether or not the amino acid change affected CYP2A6 activity, we expressed an intact or mutant CYP2A6 together with NADPH-P450 oxidoreductase in Escherichia coli, and compared the capacity of the wild and mutant enzymes to metabolize FT to 5-FU. The Vmax value for FT metabolism by the mutant CYP2A6 was approximately one-half of the value of the intact CYP2A6, although the Km values were nearly the same. From these results, we conclude that the poor metabolic phenotype of patient 1 was caused by the existence of the two mutant alleles, CYP2A6*4C and the new variant CYP2A6*11.

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.

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/m(2). The plasma C(max) values of FT, 5-FU, oxonic acid and CDHP increased dose-dependently and after 1-2 h were in the ranges 5.8-13 microM, 0.4-2.4 microM, 0.026-1.337 microM, and 1.1-3.6 microM, respectively. Uracil levels, indicative of DPD inhibition, also increased dose-dependently from basal levels of 0.03-0.25 microM to 3.6-9.4 microM after 2-4 h, and 0.09-0.9 microM was still present after 24 h. The pharmacokinetics of CDHP and uracil were linear over the dose range. The areas under the plasma concentration curves (AUC) for CDHP and uracil were in the ranges 418-1735 and 2281-8627 micromol x min/l, respectively. The t(1/2) values were in the ranges 213-692 and 216-354 min, respectively. Cumulative urinary excretion of FT was predominantly as 5-FU and was 2.2-11.9%; the urinary excretion of both fluoro-beta-alanine and uracil was generally maximal between 6 and 18 h. During 28-day courses with twice-daily S-1 administration, 5-FU and uracil generally increased. Before each intake of S-1, 5-FU varied between 0.5 and 1 microM and uracil was in the micromolar range (up to 7 microM), indicating that effective DPD inhibition was maintained during the course. In a biopsy of an esophageal adenocarcinoma metastasis that had regressed, thymidylate synthase, the target of 5-FU, was inhibited 50%, but increased four- to tenfold after relapse in subsequent biopsies. In conclusion, oral S-1 administration resulted in prolonged exposure to micromolar 5-FU concentrations due to DPD inhibition, and the decrease in uracil levels after 6 h followed the pattern of CDHP and indicates reversible DPD inhibition.

[Enzyme immunoassay of potassium oxonate using specific antibody isolated by immunosorbent gel].

An enzyme immunoassay for the determination of potassium oxonate in the plasma has been developed. The procedure is based on a competitive enzyme-linked immunosorbent assay using the second antibody solid phase method. The antiserum for potassium oxonate was prepared using oxonic acid 6-carboxypentylamide-BSA conjugate as immunogen. The specific antibody for oxonic acid was isolated from the antiserum using oxonic acid 6-carboxypentylamide immobilized immunosorbent gel. The purified antibody resulted in high sensitivity and low cross-reactivity as compared with the unpurified antiserum. Potassium oxonate in the plasma could be assayed in the range from 20 to 1000 ng/ml by the proposed EIA. The recovery was ranged from 82 to 117% and the coefficient of variation was from 6.6 to 14.7% (n = 6).

Phase II tailored S-1 regimen study of first-line chemotherapy in elderly patients with advanced and recurrent non-small cell lung cancer.

PURPOSE: We investigated the efficacy and toxicity of a novel oral 5-fluorouracil (5-FU) formulation (S-1), administered according to a tailored dose regimen. METHODS: S-1 was administered orally for 28 days, followed by 14 days of no treatment, in 23 patients who received a tailored dose of S-1, adjusted on the basis of individual creatinine clearance and body surface area. In 8 of the patients, pharmacokinetic study was performed on the 6 points on 7th day after S-1 administration. RESULTS: Of the 23 patients enrolled in this study, 2 (8.7 %) had a partial response and 14 (60.9 %) had stable disease. The disease control rate was 69.6 % (16/23) (95 % confidence interval, 50.8-88.4 %). Grade 3/4 hematologic and non-hematologic toxicities were minor. In the pharmacokinetic study group, the maximum plasma concentration (C (max)) and the area under the plasma concentration curve of 5-FU at all 6 points after administration of the tailored S-1 dose regimen were similar to the values reported in a previous study describing cancer patients with normal renal function who received a standard dose of S-1 (80 mg/m(2)/day). CONCLUSIONS: Our results suggest that tailored S-1 monotherapy is safe and therapeutically useful as first-line treatment for elderly patients with advanced and recurrent non-small cell lung cancer.

Determination of tegafur, 5-fluorouracil, gimeracil and oxonic acid in human plasma using liquid chromatography-tandem mass spectrometry.

S-1 is an oral anticancer drug, which consists of tegafur (FT), gimeracil (CDHP) and potassium oxonate (Oxo) at a molar ratio of 1:0.4:1. Among these, tegafur is a prodrug, and is rapidly metabolized to the active drug, 5-fluorouracil (5-FU), in vivo. To evaluate the pharmacokinetics of S-1 in patients, LC-MS/MS methods were developed and validated for determination of FT, 5-FU, CDHP and Oxo in human plasma. FT, 5-FU and CDHP were extracted from plasma following protein precipitation, separated on a Synergi Hydro-RP column and simultaneously quantified by LC-MS/MS. The mobile phase consisted of methanol-water-ammonia-acetic acid (27:73:0.0018:0.018, v/v/v/v). The mass spectrometer was operated in negative mode using electrospray ionization. The calibration curves were linear in the range of 12.0-3000ng/mL for FT, and 2.00-500ng/mL for 5-FU and CDHP. The accuracy ranged from 93.1% to 110.7% and the precision ranged from 2.4% to 14.6% for each analyte. To determine Oxo in human plasma, an LC-MS/MS method employing pre-column derivatization was developed and validated. 4-Bromomethyl-7-methoxycoumarin was chosen as the derivatization reagent and [(13)C(2),(15)N(3)]-Oxo was used as the internal standard. The MS/MS detection was operated in positive mode using an APCI source. The calibration range was 2.00-150ng/mL. The accuracy and precision were within 95.9-99.1% and 4.4-10.0%, respectively. The validated methods were successfully applied to characterize the pharmacokinetic profiles of FT, 5-FU, CDHP and Oxo following oral administration of 60mg S-1 tablets to patients with solid gastrointestinal tract tumors.

Plasma pharmacokinetics after combined therapy of gemcitabine and oral S-1 for unresectable pancreatic cancer.

BACKGROUND: The combination of gemcitabine (GEM) and S-1, an oral 5-fluorouracil (5-FU) derivative, has been shown to be a promising regimen for patients with unresectable pancreatic cancer. METHODS: Six patients with advanced pancreatic cancer were enrolled in this pharmacokinetics (PK) study. These patients were treated by oral administration of S-1 30 mg/m2 twice daily for 28 consecutive days, followed by a 14-day rest period and intravenous administration of GEM 800 mg/m2 on days 1, 15 and 29 of each course. The PK parameters of GEM and/or 5-FU after GEM single-administration, S-1 single-administration, and co-administration of GEM with pre-administration of S-1 at 2-h intervals were analyzed. RESULTS: The maximum concentration (Cmax), the area under the curve from the drug administration to the infinite time (AUCinf), and the elimination half-life (T1/2) of GEM were not significantly different between GEM administration with and without S-1. The Cmax, AUCinf, T1/2, and the time required to reach Cmax (Tmax) were not significantly different between S-1 administration with and without GEM. CONCLUSION: There were no interactions between GEM and S-1 regarding plasma PK of GEM and 5-FU.

An early phase II study of S-1 in patients with metastatic pancreatic cancer.

OBJECTIVE: The aim of this study was to evaluate the efficacy and toxicity of S-1 in patients with metastatic pancreatic cancer. METHODS: Patients were required to have a histological diagnosis of pancreatic adenocarcinoma with measurable metastatic lesions, and no prior chemotherapy. S-1 was administered orally at 40 mg/m2 twice daily for 28 days with a rest period of 14 days as one course. Administration was repeated until the appearance of disease progression or unacceptable toxicity. A pharmacokinetic study was done on day 1 in the initial 8 patients. RESULTS: Nineteen patients were entered into this study. Four patients (21.1%) achieved a partial response with a 95% confidence interval of 6.1-45.6%. No change was noted in 10 patients (52.6%), and progressive disease in 5 patients (26.3%). The median survival time was 5.6 months with a one-year survival rate of 15.8%. The major adverse events were gastrointestinal toxicities such as nausea and anorexia, though most of them were tolerable and reversible. There were no large differences in the pharmacokinetic parameters of S-1 in patients with pancreatic cancer and those in patients with other cancers. CONCLUSION: S-1 is active and tolerated in patients with metastatic pancreatic cancer, which will be confirmed in the following large-scale phase II study.

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.

A high-performance liquid chromatography (HPLC) and gas chromatography-negative ion chemical ionization mass spectrometry (GC-NICI-MS) method was developed for the analysis of the combined antitumor drug S-1 (tegafur, 5-chloro-2,4-dihydroxypyridine and potassium oxonate) and active metabolite 5-fluorouracil in human plasma and urine. Tegafur was fractionated from biological fluids by extraction with dichloromethane and analyzed by HPLC. 5-Fluorouracil and 5-chloro-2,4-dihydroxypyridine were extracted with ethyl acetate from the residual layer after extraction of tegafur, and converted to pentafluorobenzyl (PFB) derivatives. Potassium oxonate was cleaned up with an anion-exchange column (Bond Elut NH2). The extracted potassium oxonate was degraded to 5-azauracil and converted to PFB derivatives. The PFB derivatives were analyzed by GC-NICI-MS. A stable isotope was employed as the internal standard in the GC-NICI-MS analysis. The limits of quantitation of tegafur, 5-fluorouracil, 5-chloro-2,4-dihydroxypyridine and potassium oxonate in plasma were 10, 1, 2 and 1 ng/ml, respectively. The reproducibility of the analytical method according to the statistical coefficients is approximately 10%. The accuracy of the method is good; that is, the relative error is < 10%. The methods were applied to pharmacokinetic studies of S-1 in patients.

Safety and efficacy of S-1, a novel oral fluorouracil antitumor drug, for a chronic renal failure patient maintained on hemodialysis.

OBJECTIVE: S-1 is a novel oral fluorouracil antitumor drug that combines three pharmacological agents: tegafur (FT), a prodrug of 5-fluorouracil (5-FU); 5-chloro-2,4-dihydroxypyridine (CDHP), an inhibitor of dihydropyrimidine dehydrogenase, and potassium oxonate (Oxo), a reducer of gastrointestinal toxicity. S-1 has safe and potent antitumor effects in patients with gastric cancer via these respective functions. However, the plasma 5-FU concentration is suspected to accumulate in patients with renal dysfunction, because 50% of the CDHP is excreted into the urine. There are no useful data on safety and efficacy of S-1 in chronic renal failure patients maintained on hemodialysis (HD). We examined the influence of HD on the pharmacokinetics (PK) of S-1 and its therapeutic efficacy in liver metastases from gastric cancer. METHODS: For the HD patient, the dose of S-1 in a single-administration study was set at 50 mg/body/day (41.7% of the recommended dose of 80 mg/m2/day). S-1 was given to the patient 24 h after HD. Blood samples were obtained before administration and 2, 4, 6, 8, and 24 h thereafter and 1, 2, 4, and 72 h after the following HD session. The PK parameters (5-FU, CDHP, Oxo, and FT) were measured, and Cmax, Tmax, AUC0-24, and T1/2 were calculated. The dose of consecutive or maintained administrations was determined. RESULTS: Both an increase in Cmax and an elongation of T1/2 for 5-FU, CDHP, and Oxo, but not for FT, occurred in this case as compared with controls. The AUC0-24 of 5-FU in this case was similar to that of controls at the standard dose. After HD, 87.8, 54.5, 77.4, and 66.2% of 5-FU, CDHP, Oxo, and FT, respectively, were eliminated. A slight accumulation of CDHP did not alter the 5-FU PK. Consecutive or maintained S-1 oral administration at the same dose showed similar effects on all PK parameters of a single-administration test. Liver metastases almost totally regressed with no adverse events 4 weeks after S-1 treatment (50 mg/body/day three times a week). CONCLUSION: Adjusted doses of S-1 according to the results of PK studies may provide therapeutic safety and high efficacy in liver metastases from gastric cancer, even in chronic renal failure patients maintained on HD.

Tissue distribution and biotransformation of potassium oxonate after oral administration of a novel antitumor agent (drug combination of tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate) to rats.

S-1, a new oral 5-fluorouracil (5-FU)-derivative antitumor agent, is composed of tegafur, 5-chloro-2,4-dihydropyridine, and potassium oxonate (Oxo). Oxo, which inhibits the phosphorylation of 5-FU, is added to reduce the gastrointestinal (GI) toxicity of the agent. In this study, we investigated the tissue distribution and the metabolic fate of Oxo in rats after oral administration of S-1. Oxo was mainly distributed to the intracellular sites of the small intestines in a much higher concentration than 5-FU, but little distributed to other tissues, including tumorous ones in which 5-FU was observed after oral administration of S-1. Plasma concentration-time profiles of Oxo and its metabolites after i.v. and oral administration of S-1 revealed that Oxo was mainly converted to cyanuric acid in the GI tract. Furthermore, the analysis of drug-related radioactivity in GI contents and in vitro studies suggested that Oxo was converted to cyanuric acid by two routes, the first being direct conversion by the gut flora in the cecum, and the second, conversion by xanthine oxidase or perhaps by aldehyde oxidase after degradation to 5-azauracil (5-AZU) by the gastric acid. These results indicate that, although a part of the administered Oxo was degraded in the GI tract, Oxo was mainly distributed to the intracellular sites of the small intestines in a much higher concentration than 5-FU and that little was distributed to other tissues, including tumors. We conclude that this is the reason why Oxo suppresses the GI toxicity of 5-FU without affecting its antitumor activity.