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Tegafur, gimeracil, and oteracil potassium are widely used pharmaceuticals to treat lung cancers of the gastrointestinal tract, such as those of the oral cavity, esophagus, colon and rectum, and pancreas, as well as non-small cell lung cancers. The literature review revealed that no study has yet offered a completely stability-demonstrating, validated liquid chromatography-mass spectrometric approach for the concurrent estimation of tegafur, gimeracil, and oteracil potassium, along with all known degradation products. The simultaneous detection of tegafur, gimeracil, and oteracil potassium and their forced degradation product characterization necessitated the invention of a simpler, faster, and less expensive method. Therefore, this study aimed to follow the ICH method validation standards to develop and validate a fast, easy, and rugged liquid chromatography-mass spectrometry (LC-MS) technique for the concurrent estimation of tegafur, gimeracil, and oteracil potassium in the drug substance and the finished dosage form. Tegafur, gimeracil, and oteracil potassium were examined on the Waters HPLC Alliance system, coupled to the SCIEX QTRAP 5500 mass spectrometer, and endowed with an interface capable of carrying electrospray ionization. The tegafur, gimeracil, and oteracil peaks eluted at retention times of 2.338 min, 3.756 min, and 5.338 min, respectively. The limit of detection values of tegafur, gimeracil, and oteracil were detected to be 0.6, 0.174, and 0.474 μg/mL, respectively. The results for the quantification limit were calculated at 2.0, 0.58, and 1.58 µg/mL concentrations, respectively. Tegafur, gimeracil, and oteracil had linear ranges of 50-300 µg/ml, 14.5-87 µg/ml, and 39.5-237 µg/ml, with regression coefficients of 0.99956, 0.99986, and 0.999479, respectively. The accuracy values of tegafur, gimeracil, and oteracil in the ranges of 50%, 100%, and 150% were determined at 99.9%, 99.9%, and 99.4%, respectively. The RSD for the six replicates was less than 2% for precision. According to the ICH Q2 guidelines, this approach was effectively evaluated with LC-MS to validate the chemical structures of the freshly created tegafur, gimeracil, and oteracil degradation products. An accurate and sensitive LC-MS technique was developed and validated for the concurrent quantification of tegafur, gimeracil, and oteracil potassium in the drug material and the medicinal dosage form., Competing Interests: The authors state that they do not have any known conflicting financial interests or personal connections that may seem to have influenced the work disclosed in this study.

Rationale: We developed a new high-throughput method to analyze tegafur (FT) and 5-fluorouracil (5-FU) in tear and plasma samples using hydrophilic interaction liquid chromatography (HILIC)/tandem mass spectrometry (MS/MS)., Methods: The tear samples (10 μL) spiked with FT, 5-FU, and 5-chlorouracil (internal standard) were diluted using 40 μL of 2 M ammonium acetate and 250 μL of acetonitrile with 2% formic acid; 20 μL of plasma spiked with the two drugs and internal standard was diluted with 80 μL of 2 M ammonium acetate and 500 μL of acetonitrile with 2% formic acid. After centrifugation, the clear supernatant extract (15 μL) was directly injected into the HILIC/MS/MS instrument, and each drug was separated on a Unison UK-Amino column (50 mm × 3 mm i.d., 3 μm particle size) with a linear gradient elution system composed of 10 mM ammonium acetate (pH 6.8) and acetonitrile at a flow rate of 0.7 mL/min. We performed quantification by multiple reaction monitoring (MRM) with negative-ion atmospheric-pressure chemical ionization., Results: Distinct peaks were observed for the drugs on each MRM channel within 2 min. The regression equations showed good linearity within the range 0.04-4.0 μg/mL for the tear and plasma samples with detection limits at 0.02-0.04 μg/mL. Recoveries for target analytes (FT and 5-FU) for the tear and plasma samples were in the 94-128% and 94-104% ranges, respectively. The intra- and inter-day coefficients of variation for the two drugs were lower than 10.8%. The accuracies of quantitation were 97-115% for both samples., Conclusions: We established a high-throughput, reproducible, and practical procedure for analyzing FT and 5-FU in human tear and plasma samples using HILIC/MS/MS analysis with an aminopropyl-bonded mixed-mode separation column. This method can be applied to the high-throughput routines used in clinical analyses., (© 2019 John Wiley & Sons, Ltd.)

Background: S-1 is an oral anticancer drug composed of tegafur (FT), which is a prodrug of 5-FU, 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate. Recently, some studies have been reported on watering eyes caused by S-1. However, the mechanism of watering eyes caused by S-1 is still unclear. The aim of this study was to investigate the correlation between tears and plasma concentrations of FT, 5-FU, and CDHP, which are components and active modulator of S-1., Methods: We prospectively investigated the pharmacokinetics (PK) of FT, 5-FU, and CDHP in plasma and in tears of gastric cancer patients who were treated with S-1 monotherapy at the dose of 80 mg/m 2 /day. Plasma and tears from both eyes were obtained 1, 2, 4, and 8 h after S-1 administration on day 1 and 14 of the first cycle., Results: Total of eight patients were enrolled. All the FT, 5-FU and CDHP were detected both in plasma and in tears, and their PK parameters were measured. There was a positive correlation between the concentrations of FT, 5-FU and CDHP in the plasma and those in the tears on day 1 and day 14 (correlation coefficients r, right eye/left eye: r = 0.882/0.878, 0.877/0.890, and 0.885/0.878, respectively)., Conclusion: There was a positive correlation between the concentrations of FT, 5-FU and CDHP in the plasma and those in the tears. The result is expected to facilitate the further investigation into the causes of watering eyes and the establishment of the effective methods for the prevention and the treatment.

Molecularly imprinted polymers (MIPs) targeting tegafur, an anti-cancer 5-fluorouracil pro-drug, have been prepared by stoichiometric imprinting using 2,6-bis(acrylamido)pyridine (BAAPy) as the functional monomer. Solution association between tegafur and BAAPy was studied by (1)H NMR titration, which confirmed the formation of 1:1 complexes with an affinity constant of 574±15M(-1) in CDCl3. Evaluation of the synthesised materials by HPLC and equilibrium rebinding experiments revealed high selectivity of the imprinted polymer for the pro-drug vs. 5-fluorouracil and other competing analytes, with maximum imprinting factors of 25.3 and a binding capacity of 45.1μmolg(-1). The synthesised imprinted polymer was employed in solid-phase extraction of the pro-drug using an optimised protocol that included a simple wash with the porogen used in the preparation of the material. Tegafur recoveries of up to 96% were achieved from aqueous samples and 92% from urine samples spiked with the template and three competing analytes. The results demonstrate the potential of the prepared polymers in the pre-concentration of tegafur from biological samples, which could be an invaluable tool in the monitoring of patient compliance and drug uptake and excretion., (Copyright © 2015 Elsevier B.V. All rights reserved.)

We report a semiquantitative method for determining trace amounts (<1%) of thermodynamically stable forms in polymorphic mixtures, focusing on sample preparation effects on solid phase transitions. Tegafur [5-fluoro-1-(oxolan-2-yl)-1,2,3,4-tetrahydropyrimidine-2,4-dione] was used as a model material in this study. The amounts of the thermodynamically stable β tegafur were increased to levels detectable by powder X-ray diffractometry by grinding the samples in a ball mill in the presence of water. The limit of detection for this method was as low as 0.0005% of β tegafur in α and β tegafur mixtures. The amount of β tegafur after sample preparation was found to be proportional to the initial weight fraction of β tegafur. The sum of Langmuir and Cauchy-Lorentz equations was used to describe the change in conversion degree due to the added water volume, where Langmuir equation described water sorption during the sample preparation and Cauchy-Lorentz equation described the grinding efficiency., (Copyright © 2012 Wiley Periodicals, Inc.)

Objectives: The main objective of this work was to develop a suitable analytical technique for determining trace amounts of the thermodynamically stable solid form in bulk samples of metastable form, to a sensitivity of 0.005%-1.0%. Tegafur (5-fluoro-1-(tetrahydro-2-furyl)-uracil) α and β crystalline forms were used as a model for this problem., Methods: The trace content of the thermodynamically stable β polymorphic form in tegafur samples was increased by promoting phase transition from the bulk of thermodynamically metastable α form to β form, and achieving sufficient β form content for a quantitative powder X-ray diffractometry (PXRD) analysis. The phase transition was stimulated by adding water to the samples and then grinding in controlled conditions (temperature, time, grinding speed). A calibration line was constructed using the least squares method., Key Findings: By using a solvent that does not form hydrates with the analysed polymorphs, it was possible to promote the phase transformation from metastable form to the thermodynamically stable form. After sample preparation, the thermodynamically stable solid form content in the analysed mixture had increased proportionally to the initial weight fraction (0.005%-1.0%) of the stable form seed crystals in the samples, and the coefficient of proportionality was 43.0±0.9, with a standard deviation S(n) =1.5%., Conclusions: A simple, sensitive, semi-quantitative analytical method was developed for the low-level determination of the thermodynamically stable polymorphic form in mixtures of thermodynamically stable and metastable polymorphs., (© 2011 The Authors. JPP © 2011 Royal Pharmaceutical Society.)

5-Fluorouracil (5-FU) is a cytostatic agent that has been widely used in the treatment of various solid tumours for more than 20 years, and is still considered to be among the most active antineoplastic agents in advanced colorectal cancer and malignancies of the head and neck. A large number of non-chromatographic and chromatographic methods for the quantitation of 5-FU, related prodrugs and their metabolites in biological matrices have been developed in the last 30 years to support preclinical and clinical studies. However, 5-FU monitoring has not been widely used, at least not in the USA, and certainly not outside the clinical research setting, given the absence of simple, fast and inexpensive testing methods for 5-FU monitoring. Recent developments with testing based on liquid chromatography-tandem mass spectrometry and a nanoparticle antibody-based immunoassay may facilitate routine monitoring of 5-FU in daily clinical practice. In this review the advantages and disadvantages of the bioanalytical methods developed and used for 5-FU, its metabolites and related prodrugs are discussed.

On-line determination of the anti-tumor drug 5-fluorouracil (5-FU) and its prodrug, tegafur (TF) was achieved for the first time by capillary electrophoresis with large-volume sample stacking (CE-LVSS). The optimal electrophoretic buffer consisted of 30 mM phosphate buffer at pH 8.0. Without the LVSS procedure, the limits of detection (LOD) were 600.5 ng/mL and 771.4 ng/mL for 5-FU and TF, respectively. With the LVSS procedure, the sensitivity was significantly improved by about two orders of magnitude (the LODs of 5-FU and TF were decreased to 7.9 ng/mL and 6.5 ng/mL, respectively). The %RSD was less than 5%. This method compared favorably with other reported techniques and was applied successfully to the quantitative analysis of anti-tumor drugs in commercial injection preparations. The results show that the method is simple, fast (less than 3 min), highly selective, and sensitive.

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.

Tegafur, a prodrug of 5-fluorouracil (5-FU), is an oral fluorouracil antitumor drug used for the management of adenocarcinomas. It has an efficacy similar to that of intravenous 5-FU, with potential advantages in terms of convenience and quality of life for the patient and cost-effectiveness as compared with intravenous chemotherapy. The authors developed a high-performance liquid chromatography (HPLC) assay for the determination of tissue or plasma tegafur and 5-FU concentration in a single step extraction and a single HPLC injection. The retention times of 5-FU and tegafur were 5 and 16.5 minutes, respectively, and the internal standard retention times were 11.5 and 17.5 minutes for 5-bromouracil (5-BU) and beta-hydroxyethyltheophylline, respectively. The limit of quantification was 0.0125 microg/mL for 5-FU and 0.05 microg/mL for tegafur. The assay had good recovery (96.5% +/- 9.45% and 97.5% +/- 7.89% for 5-FU in plasma and tissue, respectively, and 88.5% +/- 12.17% and 104.9% +/- 8.77% for tegafur in plasma and tissue, respectively). Precision was good: the within-day and between-day standard deviation of the mean (RSD) for 5-FU (0.0125-5 microg/mL) and tegafur (0.5-150 microg/mL) was always <8%. The authors conclude that the method described here is ideally suited for the therapeutic monitoring of 5-FU and tegafur.

A first derivative spectrometric method has been developed for the determination of the 5-fluorouracil and N1(2'-furanidyl)uracil related substances and degradation products of tegafur. The wavelengths selected for the determination of 5-fluorouracil and N1(2'-furanidyl)uracil were 298 and 288 nm, respectively. At this wavelength, the calibration graphs between the amplitude of the signals and the concentration of each compound were linear up to 24.75 mg l(-1) for 5-fluorouracil and up to 20.20 mg l(-1) for N1(2'-furanidyl)uracil. The detection limits were 0.40 and 0.050 mg l(-1) for 5-fluorouracil and N1(2'-furanidyl)uracil, respectively. The method is simple and rapid and does not require any preliminary treatment of the sample. The method was validated.

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.

The neurotoxicity of two 5-fluorouracil (5-FU) derivatives, tegafur (FT) and carmofur (HCFU), which selectively induce leukoencephalopathy involving the cerebral white matter in humans and vacuolation of myelinated fibers in dogs and cats, was examined in vitro. The common metabolites of these drugs, alpha-fluoro-beta-alanine (FBAL) and fluoroacetic acid (FA), were added to the medium of cultured murine cerebellar myelinated fibers. On day 1 of exposure to 7 microM FBAL and FA, which corresponds to their blood concentrations 2 h after oral administration of 10 mg.kg-1 HCFU to dogs that induced central nervous system vacuolation after 30 days, partial splits of the myelinic intraperiod line were observed by electron microscopy. On days 4-7, phase contrast microscopy revealed spindle-shaped swelling and granulation of myelin and electron microscopy demonstrated prominent dissociation of the myelinic intraperiod line with monolocular and multilocular vacuolation. More severe changes, such as myelin loss, were found in cultures exposed to a higher concentration (70 microM) of FBAL and FA, but no remarkable neuronal, astrocytic or oligodendrocytic changes occurred. Quantitative evaluation of myelin injury by electron microscopy revealed significant toxicity of FBAL and FA, at concentrations of 7 and 70 microM, on day 4. However, groups treated with 0.7 microM FBAL and FA, 5-FU (7 microM) and controls exposed to beta-alanine and acetic acid concentrations of 0.7, 7 and 70 microM showed no marked injury. We concluded that these anticancer drug metabolites injure myelin fibers directly, resulting in vacuolation due to myelin splitting and destruction.

The suppression of alpha-fluoro-beta-alanine (FBAL) formation from 5-fluorouracil (FU) is an important subject in relation to tumor chemotherapy. This is the first comparative study of FU, 1-(2-tetrahydrofuryl)-5-fluorouracil (FT, a prodrug of FU) and of FT+uracil as a coadministration system (UFT) under an oral dose using the in vivo 19F NMR method. The slow release of FU from FT and the suppression of the catabolism of FU to FBAL in mouse livers and tumors by the coadministration of uracil with FT were demonstrated using consecutive NMR measurements. The applicability of the in vivo 19F NMR method to the drug evaluation in tumors and livers of small animals was successfully tested.

The fluorescence derivatization of 1-(tetrahydro-2-furanyl)-5-fluorouracil (Ftorafur, FT) with 4-bromomethyl-6,7-dimethoxycoumarin (BrMdmc) with 18-crown-6 as catalyst was utilized for a sensitive and selective liquid chromatographic method to determine the concentration of FT in hair. Hair samples collected from rats, which had received FT intraperitoneally for 1 to 4 weeks, were dissolved in 1 M NaOH by heating at 80 degrees C for 30 min. A three-step extraction procedure for FT in the dissolved hair was used before and after the derivatization of FT with BrMdmc. The detection limit achieved was < 0.16 ng/mg hair. A dose-dependent accumulation of FT was evident in the rat hair (r = 0.914, p < 0.001): 0.24 +/- 0.07, 1.35 +/- 0.39, and 2.85 +/- 0.74 ng/mg hair (mean +/- SD, n = 4-5) at the doses of 5, 15, and 50 mg/kg/day for 4 weeks, respectively. In the rats that had received the highest dose of FT, the accumulation of FT in the hair depended also on the duration of FT administration: 0.82 +/- 0.33 (1 week), 1.52 +/- 0.38 (2 weeks), and 2.85 +/- 0.74 (4 weeks) ng/mg hair (n = 4-5). These findings suggest that the analysis of an oral antineoplasmic FT in the hair may be useful for assessing the degree of exposure to the drug.

In order to elucidate the effect of tumor vascularity on a various regimens concentration in tumor tissue, correlation among tegafur, 5-fluorouracil (5-FU), uracil concentrations in tissue and the microangiography were examined in 27 patients with colorectal cancer after preoperative administration of UFT (400 mg/day for 7 days). The concentrations of tegafur, 5-FU and uracil in tumor were higher than those in normal tissue (p < 0.01). There was no definite correlation between tissue concentration in each regimen and the extra or intramural vascular changes. A significant high concentration of 5-FU was found in the protuberant cancer and the ulcerative cancer with horizontal growth than that in the ulcerative cancer with vertical growth (p < 0.05). The present study indicates that the vascular changes within a tumor and the vascular pattern of tumor may be a contributing factor affecting the tissue concentration in the regimens.

Inhibition of thymidylate synthase (TS) and the concentration of tegafur, 5-FU and uracil in the tumor and the non-tumor tissues were compared in 18 uroepithelial cancer patients who had been administered UFT (600 mg/day) for seven days before operation. 5-FU and uracil levels in the tumor tissue were increased to 5.1 and 3.6 fold, respectively, compared those in the normal tissue, although there was no difference in tegafur levels between normal and tumor tissue. The mean inhibition rate of TS activity in the tumor tissue was significantly higher (36%) than that in the normal tissue (21%). However, no correlation between 5-FU level and inhibition rate of TS activity was found in either tissue. Not only the higher tumor concentration of 5-FU but also the higher inhibition of TS activity in the tumor tissue suggests that UFT is likely a useful drug for the treatment of uroepithelial carcinomas.

The concentrations of 5-fluorouracil (5-FU) and related compounds were studied in tissues including renal cells removed from 27 cancer patients, to whom UFT (a mixture of uracil and tegafur in a molecular ratio of 4:1) was administered orally over 5 days. The level of 5-FU in cancer tissue was two-fold that of the normal kidney (87 +/- 79 ng/g vs. 38 +/- 29 ng/g, p less than 0.005), with almost the same level of tegafur. The serum 5-FU level was as low as 4 ng/ml. These results confirm the high efficiency of UFT with minimal side-effects compared to tegafur.

Oral administration of uracil plus ftorafur [1-(tetrahydro-2-furanyl)-5-fluorouracil] has a greater antitumor effect than that of ftorafur alone. A high-pressure liquid chromatographic methods was developed for the determination of ftorafur in plasma and visceral tissues with a sensitivity of 0.025 microgram/ml or g of wet weight. A combination of GLC--mass fragmentography and GLC--mass spectrometry with total-ion monitoring was developed for the specific, simultaneous determination of 5-fluorouracil, and active metabolite, and uracil as their trimethylsilylated derivatives. The detection limits for 5-fluorouracil and uracil in the first method were 0.001 microgram/ml for plasma and 0.001--0.005 microgram/ml for visceral tissues, and those in the second method were 0.2 microgram/ml or g of wet weight. The precision and sensitivity of the assay appear to be satisfactory for determination of the levels of these compounds in plasma and visceral tissues.

FT-207 was administered to 30 patients with squamous cell carcinoma of the head and neck. After FT-207 administration tumor concentration of FT-207 and 5-FU was measured using a chemical assay method. Differences of FT-207 and 5-FU in total doses, administration routes (oral, intrarectal, and intravenous), tumor sites (larynx, maxillary sinus, tongue, neck and hypopharynx), and types of differentiation (well-differentiated, moderately-differentiated, and poorly-differentiated) were studied and the following results were obtained: 1. In FT-207 tumor concentration study, no significant difference was observed in any group. 2. 5-FU tumor concentration increased in higher total administration doses and in advanced differentiated type groups as well as in the non-irradiated group. 3. 5-FU tumor concentration was measured by T/N ratio; oral and intravenous administration methods showed 4.5 (P less than 0.05) and 2.4 (P less than 0.10) respectively. In larynx tumor the highest concentration of 3.9 (P less than 0.05) was obtained among various tumors. The value of 4.0 (P less than 0.05) was yielded in the well-differentiated type, which was significantly higher compared to that of other differentiation types. Overall T/N ratio (5-FU concentration in the tumor/5-FU concentration in the normal tissue) was 2.7 (P less than 0.025).

A 750 mg FT suppository was inserted daily for seven days prior to surgery of uterine cervical carcinoma. The concentrations of FT and 5-FU in the serum, tumor tissue, adjacent normal tissues and regional lymph nodes were then measured. In addition, the concentrations of FT and 5-FU in the serum of patients who had been receiving chemotherapy for long term (an average of 15 months) after the initial remission were measured. The results are as follows: The 5-FU concentration in the serum of patients following short duration of administration was 0.014 +/- 0.006 micrograms/micromilligram. The 5-FU concentration in the tumor tissue was 0.209 +/- 0.132 microgram/g. This was approximately 3.2 times higher than the concentration in the normal tissue which was 0.065 +/- 0.017 microgram/g, and approximately 2.4 times higher than in the regional lymph nodes of 0.088 +/- 0.055 microgram/g. Relatively higher concentrations of 5-FU were seen in the non-keratinizing type than in the keratinizing type suggesting. The correlation between the concentration in the tumor tissue and the histologic findings of the carcinoma tissue. The 5-FU concentration in the serum of patients receiving long-term chemotherapy was 0.019 +/- 0.015 microgram/micromilligram, showing no significant difference from the patients receiving short-term chemotherapy.

The concentration of the active principle of ftorafur in blood and urine varied depending on the activity of metabolic processes in a patient, size and sensitivity of tumor, etc. The concentrations increased in repeat injections of the substance. The efficacy was related with the intensity of formation of active components, but is not dependent on the substance level dtermined in biological fluids of the organism.

Levels of futraful (FT-207), 5-FU and Uracil in blood and tissue were measured on 11 cases of oral malignant tumors after administration of UFT. 1) After administration of UFT, the highest level of 5-FU was detected in tumor tissue followed by the normal lymph node, metastatic lymph node, and normal tissue which showed the lowest level. 2) Levels of 5-FU in serum was lower than in tumor, and T/S ratio of levels of 5-FU was 9,190. 3) There were significant regressions in levels of 5-FU and Uracil in normal lymph node (p less than 0.02). Coefficient of correlation was 0.469. 4) Comparisons of levels of 5-FU after administration of UFT and futraful were 1.89 in tumor, 1.72 in normal tissue, 1.80 in metastatic lymph node and 1.55 in normal lymph node. Level of 5-FU after administration of UFT was higher than that of futraful. 5) Higher level of 5-FU after administration of UFT in tumor tissue and lymph node were maintained for a longer period.

Fifteen patients with stomach cancer and colorectal cancer were orally administered 600 mg of UFT before operation and the concentration of tegafur, 5-fluorouracil (5-FU) and uracil in the tissues and serum were measured by chemical assay. The mean 5-FU levels in tumor and lymph node were higher than those in normal tissues and were maintained in tumor for long time. Uracil level in tumor tissue was higher than in normal tissue with or without administration of UFT. Positive correlation between the concentration of uracil and 5-FU in the colorectal tumor with the correlation coefficient of 0.87 (p less than 0.01) was obtained.

Serum and tissue concentrations of 5-FU and FT-207 were estimated in 26 patients with bladder tumor or prostatic carcinoma after administration of FT-207 suppositories. The 5-FU concentration in bladder tumor was higher than in normal mucosal bladder tissue. The 5-FU concentration of prostatic cancer was almost equal to that of normal prostatic tissue. Relatively higher concentrations of 5-FU were recognized in bladder tumor of a high stage than of a low stage. There were no differences of serum and tissue 5-FU concentration in bladder tumor between patients more than 65 years old and those under 65 years old. No side-effects occurred in any case during suppository administration.

Fifty-one gastric adenocarcinoma patients were divided into two groups, according to the route of administration of the anticancer drug. One group was given FT-207 (tegafur, an enteric coated granule) orally and the other group, FT-207 in the form of a suppository. Blood and tissue concentrations of the drug were examined after a three-day administration of 750 mg at 09.00 and 21.00 hours. There were no significant differences between the two groups with respect to the concentrations of FT-207 and its metabolite 5-FU in the tissues. Levels of 5-FU in the excised tumor averaged 0.256 and 0.160 micrograms/g, in oral and rectal administrations, respectively, and levels in normal lymph nodes averaged 0.174 and 0.179 micrograms/g, respectively. The difference in 5-FU levels between normal and tumor tissues was statistically significant (P less than 0.05).

UFT was administered preoperatively in 20 cases of primary hepatocellular carcinoma, and tegafur, 5-fluorouracil (5-FU), uracil, total thymidylate synthase (TS) and free TS in blood and liver tissue were determined. The results were as follows. 1. Tegafur level was significantly high in blood, while the levels of 5-FU and uracil were high in the liver tissue. The 5-FU level in the cancerous area was 0.099 micrograms/g, higher than the effective level regardless of the presence or not of complication with liver cirrhosis. 2. Total TS, FdUMP (computed as total TS-free TS) and TS inhibition rate [(computed as (TS-free TS)/TS x 100 (%)] were significantly higher in the cancerous liver tissue than in the non-cancerous area. In the cases where determination was made simultaneously for the cancerous liver and non-cancerous liver tissues, the FdUMP level and TS inhibition rate in the cancerous liver tissue were high in 14 out of 17 cases (82.4%) and 13 out of 17 cases (76.5%) respectively. Therefore, UFT seems to have selective toxicity. 3. No correlation was found between 5-FU level, total TS, FdUMP in the liver tissue on the one hand and TS inhibition rate on the other. 4. UFT yielded sufficient 5-FU levels in the cancerous area regardless of the presence or not of complication with cirrhosis and therefore is expected to inhibit DNA synthesis selectively in the cancerous tissue.

Antitumor effects of UFT, tegafur (FT-207), cisplatin (CDDP) and the combination of UFT with CDDP on a human ovarian cancer xenograft in nude mice and the concentration of 5-FU in the tumor tissue and major organs were studied. UFT (48.6mg/kg/day X 20) or tegafur (15.0mg/kg/day X 20) was daily administrated orally, and CDDP (5mg/kg/day X 3) was administrated intraperitoneally at an 7-day interval. The inhibition rates of the tumor growths were 49.6% with UFT, -2.3% with tegafur and 17.7% with CDDP, respectively. In the combination of UFT with CDDP, severe side effect were observed. The concentration of 5-FU in UFT-treated group was higher than tegafur group: about 2 times in the tumor, 5 times in the liver, 9 times in the kidney and 4 times in the spleen, respectively. In the combination of UFT with CDDP, the concentration of 5-FU in major organs, especially in the kidney, in nude mice that died at 10 day after drug administration were higher than in those of UFT. These findings indicate that UFT increases the intratumoral concentration of 5-FU to elicit better antitumor effect and also the concentration of 5-FU in various normal organs after long time administration.

The blood and tissue concentrations of tegafur (TGF), 5-fluorouracil (5-FU) and uracil were tested by administering 6 capsules of UFT (600 mg as tegafur (TGF)) per day to 21 patients awaiting operation for stomach cancer. At the same time, comparative tests were performed by dividing the patients into two groups, giving UFT before meals in one group and in another after meals. Both 5-FU and uracil levels tend to reach to the maximum blood concentration after one hour, while showing similar variations with time lapse. Furthermore, a significantly positive relationship was observed between 5-FU and uracil in the rate of changes of blood concentration during six hours after administration of UFT. The 5-FU concentration within tumor tissue was 10 times higher than that within the blood and 2 times higher than that within normal tissue. A similar tendency was observed with uracil, which was of value in the clinical determination of the effect of uracil in inhibiting decomposition of 5-FU. With regard to the comparative test between the groups of pre- and post-meal UFT administration, the concentration of tegafur (TGF) and 5-FU in tumor tissue tended to be higher in the pre-meal group which indicates a need for further study of the phenomenon.

A GLC analysis for free ftorafur was developed to follow in drug disposition in body fluids of patients. The free drug was extracted from aqueous biological samples with chloroform, derivatized by methylation, and chromatographed on 1% HI-EFF 8BP using flame-ionization detection. The analysis is sensitive (0.25 microgram/ml of plasma) and specific for the intact molecule, and it does not interfere with subsequent fluorouracil analysis of the same sample.

Postoperative serum and tissue concentrations of 5-FU, FT-207 and uracil were measured in 36 patients with lung cancer who were administered UFT for seven days preoperatively. The concentration of 5-FU was high in tumor tissue and lymph nodes, but very low in serum. Such differences were not observed in the FT-207 levels. Tumor concentration of 5-FU in patients administered daily doses of 600 mg was 0.151 +/- 0.099 microgram/g which was three times higher than the minimum inhibitory concentration, and higher than that seen with other doses. The histological type and T factor were not related to the tissue concentration of 5-FU. Lymph node metastasis was not related to the concentration of 5-FU in the lymph nodes. The optimal daily dose of UFT for patients with lung cancer was considered to be 600 mg.