High-throughput method to analyze tegafur and 5-fluorouracil in human tears and plasma using hydrophilic interaction liquid chromatography/tandem mass spectrometry.

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.

Pharmacokinetics of S-1 monotherapy in plasma and in tears for gastric cancer patients.

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/m2/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.

Stoichiometric molecularly imprinted polymers for the recognition of anti-cancer pro-drug tegafur.

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.

Optimization of sample preparation conditions for detecting trace amounts of ß-tegafur in α- and ß-tegafur mixture.

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 ß 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 ß tegafur in α and ß tegafur mixtures. The amount of ß tegafur after sample preparation was found to be proportional to the initial weight fraction of ß 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.

Determination of trace amounts of ß tegafur in commercial α tegafur by powder X-ray diffractometric analysis.

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 ß crystalline forms were used as a model for this problem. METHODS: The trace content of the thermodynamically stable ß polymorphic form in tegafur samples was increased by promoting phase transition from the bulk of thermodynamically metastable α form to ß form, and achieving sufficient ß 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.

A review of analytical methods for the determination of 5-fluorouracil in biological matrices.

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.

Improved determination of 5-fluorouracil and its prodrug tegafur in pharmaceuticals by large-volume sample stacking in CE.

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.

Tegafur and 5-fluorouracil pelvic tissue concentrations in rectal cancer patients receiving preoperative chemoradiation

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Background and purpose. To investigate the presenceof 5-Fluorouracil (5-FU) in pelvic tissue afteroral administration of tegafur. To measure tegafurand 5-FU concentrations in normal rectal mucosa,perirectal fat and residual tumor in rectal cancerpatients receiving preoperative chemoradiation. Tocorrelate drug concentrations with cancer downstagingeffects.Patients and methods. Three tissue samples takenfrom 16 surgical specimens after recto-sigmoid resectionwere analyzed. Tegafur and 5-FU concentrationswere measured using high-performance liquidchromatography. 16 patients with locallyadvanced rectal cancer were treated with preoperativepelvic irradiation (45-50 Gy) sensitized withoral tegafur (400 mg for every 8 hours daily). Sevenpatients received a precharge dose of tegafur (400mg oral every 8 hours) 24 hours before surgery.Results. In 8 of the 9 patients who did not receive aprecharge dose, detectable levels of tegafur wereobserved in fat tissue, normal mucosa and tumor,but detectable 5-FU levels were only observed inone patient. Mean concentrations (ranges) for tegafurin fat, normal mucosa and tumor in patientswithout the precharge dose were 72.19 (12.1-205.6),179.53 (11.30-727.7) and 252.35 (27.9-874.6) ng/g, respectively;mean concentrations for 5-FU in thesame samples were 0.95, 1.92 and 2.68 ng/g (1 patient),respectively.In patients receiving a tegafur precharge, both tegafurand 5-FU were present in all tissue sampleswith the exception of 2 fat samples, in which drugconcentrations were undetectable.5-FU levels were higher in tumor than other sites,with a median value of 68.24 ng/g (range 3.8-283.05ng/g). Tegafur levels were also higher in tumorsamples than other sites (mean 3446.53 ng/g, range1044.5-7847.0 ng/g), except in 2 patients who hadhigher levels of tegafur in normal mucosa.Conclusions. Tegafur and 5-FU are not always presentin pelvic tissues 5 to 6 weeks after oral administrationof tegafur. Both drugs were present in thetissues analyzed, in relevant concentrations, 24hours after oral administration of tegafur. The dataobtained suggest a tendency (not significant) towarda correlation between levels of 5-FU presentin the residual tumor and cancer downstaging

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.

Determination of 5-fluorouracil and its prodrug tegafur in plasma and tissue by high-performance liquid chromatography in a single injection: validation for application in clinical pharmacokinetic studies.

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.

Determination of the 5-fluorouracil and N1(2'-furanidyl)uracil in the presence of tegafur by zero-crossing first derivative spectrometry.

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.

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.

Metabolites of 5-fluorouracil, alpha-fluoro-beta-alanine and fluoroacetic acid, directly injure myelinated fibers in tissue culture.

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.

In vivo 19F NMR comparative study of 5-fluorouracil, 1-(2-tetrahydrofuryl)-5-fluorouracil (FT) and an FT-uracil coadministration system in mouse tumors.

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.

1-(Tetrahydro-2-furanyl)-5-fluorouracil (Ftorafur) determined in rat hair as an index of drug exposure.

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.

[Studies on tissue concentration of tegafur, 5-fluorouracil, uracil after UFT administration together with the study of microangiography of colorectal cancer].

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.

[Thymidylate synthase inhibition and concentration of 5-fluorouracil after administration of UFT in human uroepithelial carcinomas].

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.

Concentration of 5-fluorouracil in renal cells from cancer patients administered a mixture of 1-(2-tetrahydrofuryl)-5-fluorouracil and uracil.

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.

Distributions of tegafur in tissues of gastric adenocarcinoma patients: tissue uptakes and concentrations in plasma after oral and rectal administrations.

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).

[Study on the pharmacokinetics of UFT in patients with hepatocellular carcinoma associated with cirrhosis].

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.