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Objective: The aim of this study was to assess internal antineoplastic drugs (ADs) contamination in the nursing staff in French hospital centers, using highly sensitive analytical methods., Methods: This cross-sectional study included nurses practicing in care departments where at least one of the five ADs studied was handled (5-fluorouracil, cyclophosphamide, doxorubicin, ifosfamide, methotrexate). The nurses study participation lasted 24 h including collection of three urine samples and one self-questionnaire. All urine samples were assayed by ultra-high-performance liquid chromatography-tandem mass spectrometry methods with very low value of the lower limit of quantification (LLOQ)., Results: 74 nurses were included, 222 urine samples and 74 self-questionnaires were collected; 1092 urine assays were performed. The percentage of nurses with internal AD contamination was 60.8% and low levels of urinary concentrations were measured. Regarding nurses with internal contamination (n = 45), 42.2% presented internal contamination by methotrexate, 37.8% by cyclophosphamide, 33.3% by ifosfamide, 17.8% by 5-fluorouracil metabolite and 6.7% by doxorubicine. Among the positive assays, 17.9% (n = 26/145) were not explained by exposure data from the self-questionnaire but this could be due to the skin contact of nurses with contaminated work surfaces., Conclusions: This study reported high percentage of nurses with internal ADs contamination. The low LLOQ values of the used analytical methods, allowed the detection of ADs that would not have been detected with the current published methods: the percentage of contamination would have been 17.6% instead of the 60.8% reported here. Pending toxicological reference values, urine ADs concentrations should be reduced as low as reasonably achievable (ALARA principle)., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Antineoplastic drugs (AD) are potentially carcinogenic and/or reprotoxic molecules. Healthcare professionals are increasingly exposed to these drugs and can be potentially contaminated by them. Internal contamination of professionals is a key concern for occupational physicians in the assessment and management of occupational risks in healthcare settings. Objectives of this study are to report AD internal contamination rate in nursing staff and to identify factors associated with internal contamination., Methods and Analysis: This trial will be conducted in two French hospital centres: University Hospital of Bordeaux and IUCT-Oncopole of Toulouse. The target population is nurses practicing in one of the fifteen selected care departments where at least one of the five studied AD is handled (5-fluorouracil, cyclophosphamide, doxorubicin, ifosfamide, methotrexate). The trial will be conducted with the following steps: (1) development of analytical methods to quantify AD urine biomarkers, (2) study of the workplace and organization around AD in each care department (transport and handling, professional practices, personal and collective protection equipments available) (3) development of a self-questionnaire detailing professional activities during the day of inclusion, (4) nurses inclusion (urine samples and self-questionnaire collection), (5) urine assays, (6) data analysis., Ethics and Dissemination: The study protocol has been approved by the French Advisory Committee on the Treatment of Information in Health Research (CCTIRS) and by the French Data Protection Authority (CNIL). Following the opinion of the Regional Committee for the Protection of Persons, this study is outside the scope of the provisions governing biomedical research and routine care (n°2014/87). The results will be submitted to peer-reviewed journals and reported at suitable national and international meetings., Trial Registration Number: NCT03137641., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Health-care personnel handling antineoplastic drugs could be at risk for adverse health effects. We aimed to evaluate genotoxic and cytotoxic effects of antineoplastic drug exposure of personnel preparing and administering such drugs in three Oncology Hospitals in Italy enrolling 42 exposed subjects and 53 controls. Furthermore, we aimed to study the possible influence of XRCC1 and hOGG1 DNA repair genes polymorphisms on genotoxicity induced on buccal cells. We performed workplace and personal monitoring of some drugs and used exposure diary informations to characterize the exposure. Urinary 5-FU metabolite (α-fluoro-β-alanine) was measured. Buccal Micronucleus Cytome (BMCyt) assay was used to evaluate DNA damage and other cellular anomalies. GEM and 5-FU contamination was found in 68% and 42% of wipe/swab samples respectively. GEM deposition was found on workers' pads while no α-fluoro-β-alanine was found. BMCyt-assay showed higher genotoxicity and cytotoxicity on nurses administering antineoplastics than on preparators and controls. Among micronucleus (MN) positive (with MN frequency higher than 1.5‰) exposed subjects, the percentage of those carrying XRCC1 mut/het genotype was higher than in MN positive-controls. Using the sensitive BMCyt assay, we demonstrated that handling antineoplastics still represents a potential occupational health risk for workers that should be better trained/informed regarding such risks., (Copyright © 2019 Elsevier B.V. All rights reserved.)

5-Fluorouracil (5-FU) is one of the most widely used antineoplastic drugs handled by healthcare professionals (HCP). To monitor occupational exposure to 5-FU, a highly sensitive ESI-UHPLC-MS/MS method was developed for the assay of its main human metabolite, α-fluoro-β-alanine (FBAL), in urine. After a derivatization step, solid phase extraction was used for the urine. Good linearity (r > 0.996), precision (CV < 14.76%), and accuracy (bias < 12.16%) were achieved. The lower limit of quantification (LOQ), 20 pg ml-1, is the lowest one published to date. Seven urine samples from 73 HCP exposed to 5FU were positive for FBAL, indicating 5FU contamination (9.6%). FBAL urine concentrations ranged from 25 to 301 pg ml-1. Such an efficient analytical tool combining high specificity with high sensitivity is essential for the reliable detection and routine biological monitoring of healthcare professionals occupationally exposed to this widely used antineoplastic drug. This method allows biomonitoring of occupational exposure to 5-fluorouracil in a routine manner, with the aim of assessing the effectiveness of collective and individual protective measures.

Background: Occupational exposure to hazardous drugs can decrease fertility and result in miscarriages, stillbirths, and cancers in healthcare staff. Several recommended practices aim to reduce this exposure, including protective clothing, gloves, and biological safety cabinets ('safe handling'). There is significant uncertainty as to whether using closed-system drug-transfer devices (CSTD) in addition to safe handling decreases the contamination and risk of staff exposure to infusional hazardous drugs compared to safe handling alone., Objectives: To assess the effects of closed-system drug-transfer of infusional hazardous drugs plus safe handling versus safe handling alone for reducing staff exposure to infusional hazardous drugs and risk of staff contamination., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, OSH-UPDATE, CINAHL, Science Citation Index Expanded, economic evaluation databases, the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov to October 2017., Selection Criteria: We included comparative studies of any study design (irrespective of language, blinding, or publication status) that compared CSTD plus safe handling versus safe handling alone for infusional hazardous drugs., Data Collection and Analysis: Two review authors independently identified trials and extracted data. We calculated the risk ratio (RR) and mean difference (MD) with 95% confidence intervals (CI) using both fixed-effect and random-effects models. We assessed risk of bias according to the risk of bias in non-randomised studies of interventions (ROBINS-I) tool, used an intracluster correlation coefficient of 0.10, and we assessed the quality of the evidence using GRADE., Main Results: We included 23 observational cluster studies (358 hospitals) in this review. We did not find any randomised controlled trials or formal economic evaluations. In 21 studies, the people who used the intervention (CSTD plus safe handling) and control (safe handling alone) were pharmacists or pharmacy technicians; in the other two studies, the people who used the intervention and control were nurses, pharmacists, or pharmacy technicians. The CSTD used in the studies were PhaSeal (13 studies), Tevadaptor (1 study), SpikeSwan (1 study), PhaSeal and Tevadaptor (1 study), varied (5 studies), and not stated (2 studies). The studies' descriptions of the control groups were varied. Twenty-one studies provide data on one or more outcomes for this systematic review. All the studies are at serious risk of bias. The quality of evidence is very low for all the outcomes.There is no evidence of differences in the proportion of people with positive urine tests for exposure between the CSTD and control groups for cyclophosphamide alone (RR 0.83, 95% CI 0.46 to 1.52; I² = 12%; 2 studies; 2 hospitals; 20 participants; CSTD: 76.1% versus control: 91.7%); cyclophosphamide or ifosfamide (RR 0.09, 95% CI 0.00 to 2.79; 1 study; 1 hospital; 14 participants; CSTD: 6.4% versus control: 71.4%); and cyclophosphamide, ifosfamide, or gemcitabine (RR not estimable; 1 study; 1 hospital; 36 participants; 0% in both groups).There is no evidence of a difference in the proportion of surface samples contaminated in the pharmacy areas or patient-care areas for any of the drugs except 5-fluorouracil, which was lower in the CSTD group than in the control (RR 0.65, 95% CI 0.43 to 0.97; 3 studies, 106 hospitals, 1008 samples; CSTD: 9% versus control: 13.9%).The amount of cyclophosphamide was lower in pharmacy areas in the CSTD group than in the control group (MD -49.34 pg/cm², 95% CI -84.11 to -14.56, I² = 0%, 7 studies; 282 hospitals, 1793 surface samples). Additionally, one interrupted time-series study (3 hospitals; 342 samples) demonstrated a change in the slope between pre-CSTD and CSTD (3.9439 pg/cm², 95% CI 1.2303 to 6.6576; P = 0.010), but not between CSTD and post-CSTD withdrawal (-1.9331 pg/cm², 95% CI -5.1260 to 1.2598; P = 0.20). There is no evidence of difference in the amount of the other drugs between CSTD and control groups in the pharmacy areas or patient-care areas.None of the studies report on atmospheric contamination, blood tests, or other measures of exposure to infusional hazardous drugs such as urine mutagenicity, chromosomal aberrations, sister chromatid exchanges, or micronuclei induction.None of the studies report short-term health benefits such as reduction in skin rashes, medium-term reproductive health benefits such as fertility and parity, or long-term health benefits related to the development of any type of cancer or adverse events.Five studies (six hospitals) report the potential cost savings through the use of CSTD. The studies used different methods of calculating the costs, and the results were not reported in a format that could be pooled via meta-analysis. There is significant variability between the studies in terms of whether CSTD resulted in cost savings (the point estimates of the average potential cost savings ranged from (2017) USD -642,656 to (2017) USD 221,818)., Authors' Conclusions: There is currently no evidence to support or refute the routine use of closed-system drug transfer devices in addition to safe handling of infusional hazardous drugs, as there is no evidence of differences in exposure or financial benefits between CSTD plus safe handling versus safe handling alone (very low-quality evidence). None of the studies report health benefits.Well-designed multicentre randomised controlled trials may be feasible depending upon the proportion of people with exposure. The next best study design is interrupted time-series. This design is likely to provide a better estimate than uncontrolled before-after studies or cross-sectional studies. Future studies may involve other alternate ways of reducing exposure in addition to safe handling as one intervention group in a multi-arm parallel design or factorial design trial. Future studies should have designs that decrease the risk of bias and enable measurement of direct health benefits in addition to exposure. Studies using exposure should be tested for a relevant selection of hazardous drugs used in the hospital to provide an estimate of the exposure and health benefits of using CSTD. Steps should be undertaken to ensure that there are no other differences between CSTD and control groups, so that one can obtain a reasonable estimate of the health benefits of using CSTD.

Chemotherapy treatment of cancer patients has shifted from inpatient to outpatient administration. Thus, family members are potentially exposed to cytotoxic drug residues from patients' excretions inside their homes. The study's aim was to evaluate the surface contamination and the potential uptake of antineoplastic drug residues by family members at home of chemotherapy patients. Overall, 265 wipe samples from 13 homes were taken at two times after chemotherapy from different surfaces (toilet, bathroom, kitchen). 62 urine samples were collected from patients and family members on three days. Samples were analyzed for cyclophosphamide, 5-fluorouracil (urine: FBAL) and platinum (as marker for cis-, carbo- and oxaliplatin). Substantial contamination was found on every surface type (PT: 0.02-42.5pg/cm 2 , 5-FU: ND-98.3pg/cm 2 , CP: ND-283.3pg/cm 2 ) with highest concentrations on toilet and bathroom surfaces. While patients' urinary drug concentrations often were elevated for more than 48h after administration, no drug residues were detectable in the family members' urine. This study provided an insight in the exposure situation against antineoplastic drug residues at home of chemotherapy patients. As contamination could be found on various surfaces adequate hygienic and protective measures are necessary to minimize the exposure risk for cohabitants., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

A novel sensor for the determination of 5-fluorouracil was constructed by electrochemical deposition of methylene blue on surface of carbon paste electrode. The electrode surface morphology was studied using Atomic force microscopy and XRD. The electrochemical activity of modified electrode was characterized using cyclic voltammetry and differential pulse method. The developed sensor shows impressive enlargement in sensitivity of 5-fluorouracil determination. The peak currents obtained from differential pulse voltammetry was linear with concentration of 5-fluorouracil in the range 4×10(-5)-1×10(-7)M and detection limit and quantification limit were calculated to be 2.04nM and 6.18nM respectively. Further, the sensor was successfully applied in pharmaceutical and biological fluid sample analysis., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Purposes: (a) To measure the urinary excretion of antineoplastic drugs of three patients during 48 h after the administration of cyclophosphamide (two patients) and 5-fluorouracil (one patient). (b) To evaluate environmental contamination with antineoplastic drugs via excreta of patients in the home setting. (c) To evaluate exposure of family members to antineoplastic drugs by measuring the drugs in their urine during the 48 h after completion of the chemotherapy by the patients., Methods: Two patients were administered cyclophosphamide by i.v. bolus injection. One patient was administered 5-fluorouracil by i.v. bolus injection and thereafter immediately administered the same drug by continuous infusion for 46 h. Urine samples from the patients administered cyclophosphamide and their family members, and wipe samples from their home environment, were analysed for the unchanged form of cyclophosphamide. For 5-fluorouracil, the urine samples from the patient and the family member were analysed for the 5-fluorouracil metabolite α-fluoro-β-alanine. Wipe samples were analysed for 5-fluorouracil. Drugs were detected and quantified with gas chromatography in tandem with mass spectroscopy-mass spectroscopy or by high-performance liquid chromatography with ultraviolet-light detection., Results: A total of 35 and 16 urine samples were collected from the three patients and their family members, respectively. The drugs were detected in all samples. Cyclophosphamide was detected at levels of 0.03-7.34 ng/cm(2) in 8 of the 12 wipe samples obtained from the homes of the patients administered cyclophosphamide. For the patient administered 5-fluorouracil, drug levels in his home environment were below the limit of detection., Conclusion: We demonstrated contamination of the home setting and exposure of family members to cyclophosphamide via the excreta of outpatient receiving chemotherapy. Exposure of the family member of the patient administered 5-fluorouracil was also demonstrated. These findings indicate the importance of strict precautions by the members of treated cancer patients as well as healthcare workers, to reduce the risk of exposure to antineoplastic drugs.

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.

A new sensitive and specific HPLC-MS/MS method for the determination of α-fluoro-β-alanine (FBAL), the main metabolite of the antineoplastic drug 5-fluorouracil (5-FU), in urine for the biological monitoring survey of health care workers exposed to 5-FU is described. This procedure is characterized by a pre-column FBAL derivatization by 2,4-dinitrofluorobenzene followed by solid phase extraction sample clean-up. The chromatographic separation was achieved by hydrophilic interaction chromatography (HILIC) on a ZIC HILIC column (Sequant) and the quantification was performed by tandem mass spectrometry. The method offers high sensitivity with a quantification limit of 1 μg/l, which is an improvement on those previously reported. The within- and between-day precisions were less than 13% and 15% respectively at the LOQ and no significant relative matrix effect was observed for FBAL. The validated method was applied to the biological monitoring of occupational exposure to 5-FU in a French hospital. Pre- and post-shift urine samples were collected from 19 workers in a hospital pharmacy and an oncology ward over a period of 5 days. On a total of 121 analysed samples, measurable amounts of FBAL were detected in up to 29%, the concentrations range from LOQ to 22.7 μg/l, yielding evidence of occupational exposure to 5-FU. Such data are scarce and represent a step forward in assessing the occupational health risks associated with handling antineoplastic drugs., (Copyright © 2010 Elsevier B.V. All rights reserved.)

We present a novel application of the heteronuclear statistical total correlation spectroscopy (HET-STOCSY) approach utilizing statistical correlation between one-dimensional 19F/1H NMR spectroscopic data sets collected in parallel to study drug metabolism. Parallel one-dimensional (1D) 800 MHz 1H and 753 MHz 19F{1H} spectra (n = 21) were obtained on urine samples collected from volunteers (n = 6) at various intervals up to 24 h after oral dosing with 500 mg of flucloxacillin. A variety of statistical relationships between and within the spectroscopic datasets were explored without significant loss of the typically high 1D spectral resolution, generating 1H-1H STOCSY plots, and novel 19F-1H HET-STOCSY, 19F-19F STOCSY, and 19F-edited 1H-1H STOCSY (X-STOCSY) spectroscopic maps, with a resolution of approximately 0.8 Hz/pt for both nuclei. The efficient statistical editing provided by these methods readily allowed the collection of drug metabolic data and assisted structure elucidation. This approach is of general applicability for studying the metabolism of other fluorine-containing drugs, including important anticancer agents such as 5-fluorouracil and flutamide, and is extendable to any drug metabolism study where there is a spin-active X-nucleus (e.g., 13C, 15N, 31P) label present.

To study the tissue distribution and excretion of indomethacin 5-fluorouracil-1-ylmethyl ester (IFM) metabolite 5-fluorouracil in rats, an accurate and specific high performance liquid chromatography method for quantifying IFM in rat plasma and tissues was developed. Biological samples were prepared by liquid-liquid extraction and separated on a Diamonsil C18 column (250 mm x 4.6 mm ID, 5 microm). The mobile phase for tissue samples, plasma samples and feces samples were composed of methanol-water-36% acetic acid (3:96.9:0.1, v/v) and the mobile phase for urine samples was a mixture of methanol-water-36% acetic acid (10:89.9:0.1, v/v). The eluate was monitored by UV absorbance at 260 nm. After a single ig dose of 100 mg x kg(-1) IFM in rats, 5-Fu was mainly distributed in stomach, small intestine, and liver. The concentrations of 5-fluorouracil in other tissues and plasma were low. The excretion of 5-Fu in urine and feces amounted to 0.0065% and 0.063% of the dose, respectively. The method is shown to be accurate and specific, and suitable for preclinical pharmacokinetic studies of IFM.

Purpose: The aim of this study is to determine whether 5-fluorouracil (5FU) used in the infusion fluid during vitrectomy is systemically absorbed., Patients and Methods: The major catabolite of 5FU, alpha-fluoro-beta-alanine (FBAL) was measured in urine samples of 2 patients that underwent vitrectomy using 5FU in the infusion fluid., Results: In both patients, FBAL was found in the urine samples collected up to 48 hours after the surgery, with the highest concentration and total amount in the first 6 hours after the first urine production after surgery. Moreover, the concentration and total amount of FBAL was higher in the patient who received silicone oil tamponade (versus 12.5% SF6), with the longest surgery time (40 min versus 20 min) and the highest amount of infusion fluid used (350 ml versus 250 ml)., Conclusions: 5FU, used to prevent the formation of proliferative vitreoretinopathy (PVR), is systemically absorbed when used in infusion fluid during vitrectomy. As such, patient selection is needed to avoid adverse effects on procreativity. Further studies will be needed to determine which clinical setting will influence most the absorption.

The validation of an analytical method for the measurement of the unnatural amino acid alpha-fluoro-beta-alanine (AFBA), the main metabolite of the antineoplastic drug 5-fluorouracil (5FU), in urine for the biological monitoring of the exposure of hospital workers to the drug when preparing the therapeutical doses and administering to cancer patients is described. The method employed a two-step extractive derivatization of the analyte from urine to the N-trifluoroacety-n-butyl ester derivative and detection by selected-ion monitoring gas chromatography-mass spectrometry of structurally specific fragments. The limit of detection was 20 ng/mL with quantification accuracy better than +/-20% and precision (CV%) better than +/-20% in the range 0.020-10 microg/mL. Norleucine was used as the internal standard and the sample-to-sample analysis time was less than 15 min. The validated method has been applied to the biological monitoring of some hospital workers potentially exposed to 5FU and to matched control subjects. On a total number of 65 analyzed urine samples from control and exposed subjects, only three, obtained from exposed subjects, were found to be positive, with values of 20, 30 and 1150 ng/mL, respectively., (Copyright 2005 John Wiley & Sons, Ltd.)

The pharmacokinetic parameters of 5-fluorouracil were compared after intravenous administration at a dose of 30 mg/kg to control Sprague-Dawley rats and to rats with diabetes mellitus induced by streptozotocin (DMIS). In DMIS rats, the area under the plasma concentration-time curve from time zero to time infinity (AUC) was significantly smaller (603 versus 909 microg min/ml) due to the significantly faster total body clearance (Cl; 47.8 versus 33.0 ml/min/kg). The faster Cl was due to the significantly faster renal (8.54 versus 4.02 ml/min/kg) and nonrenal (38.5 versus 28.7 ml/min/kg) clearances. In DMIS rats, the total amount of unchanged 5-fluorouracil excreted in 24 h urine was significantly greater (34.1% versus 13.0% of intravenous dose) due to the urine flow rate-dependent renal clearance of 5-fluorouracil in rats (the greater the urine flow rate, the greater the urinary excretion of 5-fluorouracil). Greater urinary excretion and a significantly smaller AUC resulted in a significantly faster Cl(r) in DMIS rats. The faster Cl(nr) in DMIS rats could be due to an increase in the expression and mRNA level of CYP1A1/2 in the rats., (Copyright 2005 John Wiley & Sons, Ltd.)

The present study was undertaken to elucidate the kidney- and site-selective delivery of 5-fluorouracil (5-FU) following kidney surface application in rats. We selected an experimental system utilizing a cylindrical diffusion cell attached to the right kidney surface. After 5-FU was applied to this surface, approximately 60% was absorbed in 180 min. A semi-log plot of the remaining amount of 5-FU in the diffusion cell gave a straight line. The cumulative amount of urinary excretion of 5-FU for up to 180 min from the right ureter was significantly higher than that from the left ureter. On the other hand, the cumulative amount of urinary excretion of 5-FU from the right and left ureters after intravenous administration of the drug was similar. The 5-FU concentration at four sites in the right kidney after intravenous administration was also similar, while the drug was site-selectively delivered in the kidney after its surface application. 5-FU accumulated at the site under the diffusion cell was rapidly eliminated after its removal from the diffusion cell. From these results, we demonstrated that the absorption of 5-FU on the kidney surface in rats is explained mostly by passive diffusion. It was further elucidated that kidney surface application of this drug in rats results in its the kidney- and site-selective delivery.

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.

1. The metabolic pathway(s) of OGT 719, a novel nucleoside analogue in which galactose is covalently attached to the N1 of 5-fluorouracil (FU), have been investigated with (19)F-NMR spectroscopy in (1) the isolated perfused rat liver (IPRL) model, (2) normal rats, (3) rats bearing the HSN LV10 sarcoma, (4) nude mice xenografted with the human hepatoma HepG2 and (5) urine from patients. 2. The administration of OGT 719 results in the formation of small amounts of FU. IPRL experiments with OGT 719 in combination with asialofetuin, a natural asialoglycoprotein receptor (ASGP-r), suggest competitive binding of OGT 719 to the ASGP-r. 3. The data obtained in non-tumour rats also demonstrated an extremely low metabolization of OGT 719 into FU and alpha-fluoro-beta-alanine, the well-known major metabolite of FU. 4. A comparison of tumour extracts from rats bearing the HSN LV10 sarcoma treated with FU or OGT 719 showed the incorporation of FU into RNA in rats treated with FU but not in rats treated with OGT 719; nevertheless, the incorporation of FU into RNA was observed in the liver from rats treated with OGT 719. 5. In a human hepatoma xenografted to nude mice, both the OGT 719 and FU contents of the tumour were markedly higher than in the corresponding liver, suggesting a tumour-specific trapping of OGT 719 in hepatoma. 6. The metabolism of OGT 719 was also extremely low in patients. 7. In conclusion, the present study shows the value of (19)F-NMR for demonstrating for the first time that OGT 719 is a prodrug of FU although very poorly metabolized.

Capecitabine (Xeloda; CAP) is a recently developed oral antineoplastic prodrug of 5-fluorouracil (5-FU) with enhanced tumor selectivity. Previous studies have shown that CAP activation follows a pathway with three enzymatic steps and two intermediary metabolites, 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-deoxy-5-fluorouridine (5'-DFUR), to form 5-FU preferentially in tumor tissues. In the present work, we investigated all fluorinated compounds present in liver, bile, and perfusate medium of isolated perfused rat liver (IPRL) and in liver, plasma, kidneys, bile, and urine of healthy rats. Moreover, data obtained from rat urine were compared with those from mice and human urine. According to a low cytidine deaminase (3.5.4.5) activity in rats, 5'-DFCR was by far the main product in perfusate medium from IPRL and plasma and urine from rats. Liver and circulating 5'-DFCR in perfusate and plasma equilibrated at the same concentration value in the range 25 to 400 microM, which supports the involvement of es-type nucleoside transporter in the liver. 5'-DFUR and alpha-fluoro-beta-ureidopropionic acid (FUPA) + alpha-fluoro-beta-alanine (FBAL) were the main products in urine of mice, making up 23 to 30% of the administered dose versus 3 to 4% in rat. In human urine, FUPA + FBAL represented 50% of the administered dose, 5'-DFCR 10%, and 5'-DFUR 7%. Since fluorine-19 nuclear magnetic resonance spectroscopy gives an overview of all the fluorinated compounds present in a sample, we observed the following unreported metabolites of CAP: 1) 5-fluorocytosine and its hydroxylated metabolite, 5-fluoro-6-hydroxycytosine, 2) fluoride ion, 3) 2-fluoro-3-hydroxypropionic acid and fluoroacetate, and 4) a glucuroconjugate of 5'-DFCR.

Recent in vitro and in vivo studies compared the absorption of a 0.5% fluorouracil cream with that of a 5% fluorouracil cream, following topical application to the skin. Both studies demonstrated that fluorouracil is minimally absorbed into the systemic circulation. Despite a one-tenth concentration difference between formulations, the cumulative amount of fluorouracil excreted in the urine of patients treated with the 0.5% cream was one fortieth that of patients treated with the 5% cream. Interestingly, higher percentages of fluorouracil were retained in the skin following application of the 0.5% cream compared with the 5% cream, suggesting that delivery of the 0.5% cream may be more targeted to the affected area. Other studies have demonstrated that the 0.5% cream is as effective as the 5% cream for the treatment of actinic keratoses (AKs) and has a more favorable tolerability profile. Therefore, this new 0.5% fluorouracil cream may be a safer, yet equally effective treatment alternative.

We report a quantitative assay of 5-fluorouracil (FU) and its metabolite, 5-fluorodihydrouracil (FDHU) in human urine by used a column-switching high-performance liquid chromatographic method. The analyses were carried out using a molecular exclusion column for sample purification, and a cation-exchange column for separation. Each sample required only 40 min to analyze, and required no preparation other than filtration. Linearity was verified up to 1000 nmol/ml (r > 0.993). The recovery of FU was 96-101%; recovery of FDHU was 96-105%. The imprecision (RSD) for FU (10-100 nmol/ml) was < 1.5%, same-day (n = 5), and < 1.8%, day-to-day (n = 5). The imprecision (RSD) for FDHU (10-100 nmol/ml) was < 3.2%, same-day (n = 5), and < 4.0%, day-to-day (n = 5). The detection limits were, respectively, 0.1 nmol/ml. We measured FU and FDHU in urine of seven cancer patients after oral administration of FU. The cumulative quantity ratio of the FDHU and FU (FDHU/FU) excreted in their urine within 120 min after FU administration was a constant value in all seven patients. Based on these results, we believe that our method provides a useful tool for evaluating FU metabolism.

We report the first demonstration of the biotransformation of the anti-cancer drug 5-fluorouracil (FU) into two new metabolites, alpha-fluoro-beta-hydroxypropionic acid (FHPA) and fluoroacetate (FAC), in the isolated perfused rat liver (IPRL) and in the rat in vivo. IPRL was perfused with solutions of pure FU at two doses, 15 or 45 mg kg(-1) body weight, and rats were injected i.p. with 180 mg of FU kg(-1) body weight. Fluorine-19 NMR analysis of perfusates from IPRL and rat urine showed the presence of the normal metabolites of FU and low amounts of FHPA (0.4% or 0.1% of injected FU in perfusates from IPRL treated with 15 or 45 mg of FU kg(-1) body weight, respectively; 0.08% of the injected FU in rat urine) and FAC (0.1% or 0.03% of injected FU in perfusates from IPRL treated with 15 or 45 mg of FU kg(-1) body weight, respectively; 0.003% of the injected FU in rat urine). IPRL was also perfused with a solution of alpha-fluoro-beta-alanine (FBAL) hydrochloride at 16.6 mg kg(-1) body weight dose equivalent to 15 mg of FU kg(-1) body weight. Low amounts of FHPA (0.2% of injected FBAL) and FAC (0.07%) were detected in perfusates, thus demonstrating that FHPA and FAC arise from FBAL catabolism. As FAC is a well-known cardiotoxic poison, and FHPA is also cardiotoxic at high doses, the cardiotoxicity of FU might stem from at least two sources. The first one, established in previous papers (Lemaire et al, 1992, 1994), is the presence in commercial solutions of FU of degradation products of FU that are metabolized into FHPA and FAC; these are formed over time in the basic medium necessary to dissolve the drug. The second, demonstrated in the present study, is the metabolism of FU itself into the same compounds.

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.

An RF network and a dual-tuned surface coil are described for obtaining proton-decoupled, NOE enhanced 19F spectra from a whole body clinical imager operating at 1.5 Tesia. The network removes 19F frequency noise from the decoupler transmitter, and prevents preamplifier saturation from high-level decoupling signals. Proton decoupling of 19F spectra was optimized using a sample of urine containing 5-fluorouracil (5-FU) and its catabolite fluoro-beta-alanine (FBAL). Proton-decoupled 19F spectroscopy in vivo is demonstrated by obtaining both nonlocalized spectra and spectra localized with three-dimensional chemical shift imaging from the liver of patients undergoing 5-FU chemotherapy.

The penetration enhancer, 1-[2-(decylthio)ethyl]azacyclopentan-2-one (HPE-101), significantly enhanced the excretion of topically applied [14C]indomethacin when dissolved in dipropylene glycol, triethylene glycol, diethylene glycol, 1,3-butylene glycol, trimethylene glycol, glycerin, water, silicone or triethanolamine, but not when dissolved in ethanol, isopropyl alcohol, oleyl alcohol, olive oil, peppermint oil, isopropyl myristate or hexylene glycol. HPE-101 significantly enhanced the excrection of [14C]indomethacin, [14C]nicotinic acid, [14C]5-fluorouracil, [3H]oestradiol and [3H]triamcinolone acetonide, but not that of [3H]testosterone. HPE-101 also significantly enhanced the excretion of [14C]indomethacin applied to intact skin of rabbit, guinea-pig and rat, and to tape-stripped skin of guinea-pig, but did not enhance the excretion of [14C]indomethacin applied to tape-stripped skin of rat or rabbit.

We have measured urinary tegafur (FT), 5-FU and uracil concentrations after UFT oral administration (300 mg daily for 7 days) to confirm drug-taking compliance in the 17 cases undergone gastrectomy. Urinary FT and 5-FU concentrations reached to the plateau 2 and 3 days after administration, respectively, and were maintained until the day after termination of administration. Subsequently, FT and 5-FU concentrations also decreased about 50% at 2 day, 20% at 3 day, 10% of the plateau values at 4 day after termination, respectively. The mean plateau value of urinary FT was 12.9 +/- 6.8 micrograms/dl, and that of urinary 5-FU was 0.67 +/- 0.50 microgram/dl. On the other hand, uracil concentration, was not different before and after administration because of the uracil being present endogenously. Therefore, it was suggested that measurement of urinary FT and 5-FU concentrations is useful for confirmation of UFT-taking compliance.

The occupational exposure to cyclophosphamide (CP), ifosfamide (IF), 5-fluorouracil (5FU), and methotrexate (MTX) of 25 pharmacy technicians and nurses from four departments of a hospital was investigated. Previously developed methods for the detection of exposure to some antineoplastic agents were validated. Exposure to CP, IF, 5FU, and MTX was measured by the analysis of these compounds in the environment (air samples and wipe samples from possible contaminated surfaces and objects). Contamination of the work environment was found not only on the working trays of the hoods and on the floors of the different rooms but also on other objects like tables, the sink unit, cleaned urinals and chamber pots, and drug vials and ampules used for preparation and packing of drugs. The gloves used during preparation of the drugs and during cleaning of the hoods were always contaminated. The uptake of CP or IF was determined by the analysis of both compounds in urine. CP or IF was detected in the urine of eight pharmacy technicians and nurses. The amounts ranged from less than 0.01 to 0.5 micrograms (median: 0.1 microgram). CP and IF were found not only in the urine of pharmacy technicians and nurses actively handling these compounds (n = 2) but also in the urine of pharmacy technicians and nurses not directly involved in the preparation and administration of these two drugs (n = 6). CP and IF were excreted during different periods ranging from 1.40 to 24.15h after the beginning of the working day, suggesting different times of exposure, different exposure routes, and/or interindividual differences in biotransformation and excretion rate for these compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

A relationship between the gut flora level, particularly gram-negative enterobacilli, and the in vivo flucytosine conversion to fluorouracil has been observed in humans from the fluorine-19 magnetic resonance spectroscopy analysis of urine from two patients treated with the flucytosine- (6 to 9 g/day) amphotericin B (1 mg/kg/day) combination. Indeed the percentage of fluorouracil metabolites was extremely low (less than 0.6% of total fluorinated compounds excreted) when the number of enterobacillary colonies was low (less than 10(3] and higher (3.5 to 8.8%) when enterobacillary colonies were under reconstitution or in the normal range (10(5) to 10(8]. The intestinal microflora assessment may therefore be of high interest to predict the risk of an additive flucytosine-induced myelotoxicity suspected to be due to fluorouracil during flucytosine chronic therapy.

A highly sensitive and convenient gas chromatographic-mass spectrometric (GC-MS) method is described for the determination of 5-fluorouracil in the presence of 2'-deoxy-5-fluorouridine (which breaks down into 5-fluorouracil during ordinary GC derivatization) in biological samples such as plasma and urine. After extraction with ethyl acetate, 5-fluorouracil and 5-chlorouracil, the latter being used as an internal standard, were converted into their tert.-butyldimethylsilyl derivatives by allowing the mixture to stand for 30 min at room temperature and were assayed by electron-impact ionization GC-MS. Under these conditions, 2'-deoxy-5-fluorouridine did not decompose or interfere with the determination of 5-fluorouracil. The assay method, including the extraction and tert.-butyldimethylsilyl derivatization of 5-fluorouracil, showed good linearity in the range 0-100 ng/ml for 5-fluorouracil in plasma (detection limit 0.5 ng/ml) and urine (detection limit 1 ng/ml). The usefulness of this method was demonstrated by determining plasma concentrations of 5-fluorouracil in rats treated intravenously with 5-fluorouracil and 2'-deoxy-5-fluorouridine.

A compartmental model of the kinetics of 5-fluorouracil (5-FU) and its catabolites in humans is proposed. This model was developed using data from a previous study in which plasma levels and urinary amounts of unchanged drug and metabolites were quantitated after i.v. bolus injection of 500 mg/m2 5-FU in ten patients. Biliary excretion was also quantified in two subjects. The different processes, biochemical transformations, and urinary and biliary excretion were adequately described by first-order kinetics. The technique of multiresponse modelling was used for global fitting of all data for each patient. Satisfactory agreement was achieved between measured and predicted values. This model enabled accurate evaluation of pharmacokinetic parameters that could not be adequately calculated using a model-free analysis. The total clearance and elimination half-life of 5-FU and its catabolites are reported for all subjects. The estimated mean half-life was 6.9 +/- 3.9 min for unchanged 5-FU and 225 +/- 352, 7.6 +/- 4, and 9.6 +/- 7.7 min, respectively, for the three measured catabolites dihydrofluorouracil (FUH2), alpha-fluoro-beta-ureidopropionic acid (FUPA), and alpha-fluoro-beta-alanine (FBAL). The percentage of anabolic, catabolic, urinary, and biliary elimination in total clearance was also quantitated. Anabolic clearance accounted for 39% +/- 14% of total 5-FU clearance, with substantial variation occurring among patients. Urinary clearance represented 6.5% +/- 3.2%, 0.8% +/- 0.9%, 13.2% +/- 4.7%, and 98.2% +/- 2.5% of total clearance for 5-FU, FUH2, FUPA, and FBAL, respectively. The model was also satisfactorily fitted to the data of a patient deficient in dihydropyrimidine dehydrogenase, an enzyme previously thought to be the rate-limiting step for 5-FU catabolism. In this case, catabolism was highly reduced and urinary excretion of 5-FU increased up to 64% of total drug clearance. This first global model of the kinetics of 5-FU and all of its catabolites in patients given an i.v. bolus infusion of 500 mg/m2 5-FU represents a further step toward detailed comprehensive modeling of the kinetics of this drug.

The kinetics of 5-fluoro-2'-deoxyuridine (FdUrd) and 5-fluorouracil (FUra) disposition after bolus intravenous injection were determined in anesthetized rhesus and cynomolgus monkeys. FdUrd disappearance from plasma was an apparent triexponential process with average half-lives of 0.5, 2, and 8 min; FUra disappearance was biphasic with average half-lives of 2 and 13 min. After FdUrd injection, FUra reached peak plasma concentrations of 15-30% of the initial FdUrd concentrations within 3 min, and then disappeared more slowly than FdUrd. Total FdUrd clearance fell from 105 to 73 to 56 ml/kg/min as the dose increased from 10 to 20 to 40 mg/kg. Metabolic clearance was about 85% of total clearance and fell similarly with increasing dosage. Total and metabolic FUra clearances were about 30% of FdUrd values at an equimolar dose. Renal FdUrd clearance exceeded glomerular filtration rate and was decreased by probenecid, indicating tubular secretion; renal FUra clearance was close to glomerular filtration rate. There was no apparent correlation between dose and renal clearance or volume of distribution. It was concluded that FdUrd, like FUra, is eliminated primarily by a dose-dependent process. The metabolic basis of the dose-dependent kinetics remains to be determined.

1. 1-Hexylcarbamoyl-5-fluoro[6-14C]uracil (14C-HCFU) administered orally to rats, rabbits and dogs at a dose of 20 mg/kg was well absorbed and rapidly excreted via the kidney. 2. HCFU was extensively biotransformed, and its six metabolites including two new metabolites were detected in plasma and urine of all three species. Two new metabolites were identified by spectral analysis as 1-(5-hydroxyhexylcarbamoyl)5-fluorouracil and 1-(5-oxohexylcarbamoyl)-5-fluorouracil. 3. The metabolic pathways of HCFU in the three species involved oxidations and scission of the side-chain with successive degradation of the fluorouracil (FU) released. 4. The two main routes of oxidations of the side chain were omega-oxidation and omega-1-oxidation. Rats metabolized HCFU preferentially by the former reaction, while in rabbits and dogs the latter reaction predominated.

A relatively simple and sensitive high-performance liquid chromatographic (HPLC) method is described for measuring the two anticancer drugs 5'-deoxy-5-fluorouridine (5'dFUR) and 5-fluorouracil (5-FU) in human plasma and urine. The procedure for plasma includes solvent extraction using ethyl acetate-isopropyl alcohol (85:15) followed by silica gel column chromatography to separate these compounds from constituents normally occurring in plasma. The analysis by reversed-phase HPLC is performed on a phenyl column using an aqueous mobile phase with ultraviolet detection (280 nm). The overall recovery from plasma was 61% and 65% for 5'dFUR and 5-FU, respectively. The sensitivity limit of the assay for both compounds was 50 ng/ml of plasma. Analysis of these compounds in urine did not require the silica column chromatography isolation step.

Excretion and metabolites in urine and feces of mice after oral administration of l-hexylcarbamoyl-5-fluorouracil-6-14C (14C-HCFU) or 5-fluorouracil-6-14C (14C-FU) were examined. After oral administration, about 90% of 14C-HCFU was excreted in urine within 48 h but not in feces. Major radioactive compounds in urine were 1-(3-carboxypropylcarbamoyl)-5-fluorouracil (CPRFU), FU, 5, 6-dihydro-5-fluorouracil (DHFU) and alpha-fluoro-beta-alanine (FBAL). Excretion ratio of these metabolites within 48 h was 13.5, 32.5, 20.2 and 23.9%, respectively, CPRFU and FU were rapidly excreted in urine after 14C-HCFU administration followed by DHFU and FBAL. Excretion of the latter two degradation products of FU was slower. On the other hand, major metabolites in urine after 14C-FU administration were DHFU and FBAL, but intact FU was slightly excreted. Excretion ratio of FU, DHFU and FBAL within 48 h was 4.8, 58.1 and 28.2%, respectively.

The kinetics of 5-fluoruracil concentration in blood and urine in 18 patients with cancer of the pancreas was determined in a regional and systemic method of its administration. The concentration of 5-fluoruracil in blood was found to be, as a rule, lower and the time of detection shorted after i/a (regional) administration as compared with i/i (systemic) one. Accordingly, less amount of the substance involved is excreted with the urine in regional chemotherapy. This allows an application of large single and sessional doses in insignificant general toxic effects and also gaining much better therapeutic effect.

Intravenous injection of phtoafur in experimental animals induced the appearance of the biologically active substance in the organism. The concentration of the active substance in blood and organs, reaching its maximum during the first hour, was retained for a long time: an appreciable fall in the substance levels was noted only 12 hours following its injection. In blood and organs of animals with a sensitive tumor levels of the active substance are considerably lower than in intact animals. This seems to condition the therapeutic effect of the drug.

1. The metabolic fate of a new antitumour agent, 1-hexylcarbamoyl-5-fluoro [6-14C]uracil (14C-HCFU) in rats after oral administration was compared with that of 5-fluoro[6-14C]uracil (14C-FU). 2. Tissue radioactivity reached a max. 1 to 3 h after administration of 14C-HCFU and 0.5 h after 14C-FU. 3. Both drugs were excreted rapidly, mostly in urine. Expired 14CO2 from 14C-HCFU was significantly less than that from 14C-FU. 4. Unchanged FU was not detected in plasma 3 h after administration of 14C-FU, whereas FU was detected in plasma 5 h after 14C-HCFU. The pyrimidine ring of 14C-HCFU might be degradated more slowly than that of 14C-FU. 5. 1-(5-Carboxypentylcarbamoyl)-5-fluorouracil and 1-(3-carboxypropylcarbamoyl)-5-fluorouracil were identified as the major urinary metabolites of 14C-HCFU.

We determined the urinary excretion of 5-fluorouracil (5FU) and its metabolites during six days of chemotherapy, using the non-invasive approach of 19F nuclear magnetic resonance. With this method, which requires no labeled drug, one can study the biological sample directly and simultaneously identify and quantify all the fluorinated metabolites. The daily urinary excretion of 5FU and its metabolites was high (94.8% of 5FU administered) and nearly constant all during the treatment. By far the major excreted catabolite was alpha-fluoro-beta-alanine, which made up 78.9% of the total. Unchanged 5FU (10.8% of dose injected) was found only during the first 2 h after injection. We observed neither accumulation of 5FU nor modifications in its metabolism during the treatment.

Plasma concentrations of 5-fluorouracil (FU) and its primary catabolite, 5', 6'-dihydro-5-fluorouracil (DHFU) were measured using gas-liquid chromatography after single-dose therapy with 7.2-14.4 mg/kg. Because of the limited sensitivity of the assay for drug levels in plasma, the urinary excretion of FU and metabolites was investigated using an ion-specific electrode after either a single bolus (7.0-9.6 mg/kg) or multiple-dose therapy (6.4-7.4 mg/kg/day). Half-life values for the elimination of FU from plasma (mean, 123.5 min) were greater in each patient than for the catabolite (mean, 109.2 min). Values of the area under the curve for FU profiles varied between patients (mean +/- SE, 12.7 +/- 1.9 micrograms X h/ml) by comparison with the relatively constant values for curves of DHFU concentrations (mean +/- SE, 2.8 +/- 0.15 micrograms X h/ml). In pharmacokinetic profiles of urinary excretion a transient phase of convex shape was apparent after 80%-98% of single doses of FU was excreted. Half-lives for the elimination of FU in urine were 2.6-5.9 h, which increased to 18-44 h on multiple dosing. The results demonstrate saturation in the elimination of FU after therapeutic doses, and are consistent with the proposal that reduction of FU to DHFU provides the rate-limiting step.

18F-labeled 5-fluorouracil(FUra), 5-fluoro-2'-deoxyuridine(FdUrd), and 5-fluorouridine ( FUrd ) were synthesized with high radiochemical purities. The 18F-labeled pyrimidines were injected into rats. The metabolites in serum, bile, and urine were analyzed up to 2 h after administration by radio-high performance liquid chromatography (HPLC). The blood clearance of three pyrimidines was very rapid. In the serum the nucleosides and base disappeared very rapidly with a biological half-life of about 2 min and most of them had disappeared by 60 min. The metabolites in the urine were similar to those in the serum. In the bile pyrimidine nucleosides and base were not detected. 18F- was found in the metabolites. Our results explain the high uptakes in the kidney and liver in biodistribution studies of the 18F-labeled pyrimidines.

The pharmacokinetics of 5-fluouracil were studied in 9 patients with a history of bladder malignancies. A single dose of 250 mg. 5-fluorouracil was given orally and the renal clearance of active 5-fluorouracil was approximately 40 ml. per minute. The maximum serum (1,100 ng./ml. serum) and urinary concentrations (49,000 ng./ml. urine) of 5-fluorouracil occurred 20 and 40 minutes after administration, respectively. The urinary concentration per se is highly cytotoxic, whereas the short-lasting serum concentration previously has been proved to be without general cytotoxic effects even after continuous use of the drug for years. Although high concentrations of 5-fluorouracil are noted in the urine the antitumor effects of this treatment must be investigated further.

Seven patients with advanced colon cancer, refractory to conventional chemotherapy, and malignant disease confined to the intra-abdominal space received a total of 24 consecutive courses of ip 5-Fluorouracil (5-FU). 5-FU 1000 mg was administered in 2 L of warm (37 degrees C) dialysate daily for five consecutive days every 28 days. 5-FU concentrations in serum, peritoneal fluid and urine were measured by high pressure liquid chromatography (HPLC). The mean disappearance half-life of 5-FU from the peritoneal fluid was 1.6 hours with a mean permeability area product (PA) of 22.4 ml/min. The mean peritoneal AUC was 450 +/- 165 times greater than the mean serum AUC. Ip 5-FU treatment is well tolerated, can be safely administered on an outpatient basis and produces a significant pharmacological advantage over conventional routes of administration.

As part of a Phase I clinical trial, 5 patients received 5-fluorouracil (FU) both singly and in combination with misonidazole (MISO) for the treatment of gastrointestinal cancer. Concentrations of total FU and F-containing metabolites in urine specimens, taken during 48 h after therapy, were determined. The clearance of FU following administration of 1.0 or 1.5 g FU m2 was significantly reduced by treatment with MISO (1.75-2.0 gm-2) given 2 h prior to FU therapy. Reduced clearance of FU by MISO was associated with an earlier onset of the period of nonlinearity of FU pharmacokinetics and an increased half-life of elimination. Furthermore, the clearance of FU correlated inversely with the severity of gastrointestinal toxicity. The mechanism of MISO enhancement of FU action is unlikely to be competition for microsomal enzymes, as proposed for the interaction of MISO and alkylating agents, since FU is catabolized at mitochondrial and cytosolic sites.

A high-pressure liquid chromatographic method that is used to determine the pharmacokinetic disposition of 5-fluorouracil from the plasma compartment is presented. The method requires only 0.5 ml of plasma for each determination and is sensitive to 0.1 mg of drug per liter. Novel methodology with the use of an ion-specific electrode technique for the determination of urinary excretion kinetics of 5-fluorouracil and its metabolites is also presented. This study demonstrated a much greater variability for the disposition of 5-fluorouracil by cancer patients than has been reported previously. The apparent volume of distribution for this drug varied more than 37-fold. Its plasma half-life varied more than 19-fold, and its urinary excretion half-life varied almost 400-fold. These data are compatible with the hypothesis that this variation could account, at least in part, for the variable therapeutic and toxic response to 5-fluorouracil. The methodology presented in this study is sufficiently simple and sensitive to allow assessment of this hypothesis by investigating cancer patients who receive therapeutic doses of 5-fluorouracil.

The metabolism, antitumor activity, and acute toxicity of 5-fluoro-1,3-bis-(tetrahydro-2-furanyl)-2,4-pyrimidinedione (FD-1) were investigated in animals, compared with 5-fluoro-1-(tetrahydro-2-furanyl)-2,4-pyrimidinedione (FT). It was found that after oral administration of FD-1, the level of 5-fluorouracil (5-FU) was maintained higher and longer than after administration of FT, and that a large amount of 5-FU was released from FD-1 by liver microsomal drug-metabolizing enzymes or spontaneous hydrolysis via 5-fluoro-3-(tetrahydro-2-furanyl)-2,4-pyrimidinedione (3-FT) and FT. FD-1 had a significant activity against the solid form of Ehrlich carcinoma, sarcoma-180, hepatoma AH130, Yoshida sarcoma, Walker carcinosarcoma-256, and leukemia L1210 and P388, but not the ascitic forms, and it produced greater inhibition of tumor growth than FT. The acute toxicity of FD-1 was less than that of FT.

A gas chromatographic method was developed for ftorafur (Ft) detection in plasma and urine with a sensitivity of 1 mug/ml. Specific determination of its metabolite 5-fluorouracil (FU) with a sensitivity of 1 ng/ml was achieved by column chromatographic separation from Ft and subsequent gas chromatography-mass spectrometry of bis-silyl-FU in the selected ion mode (GC-MS-SIM) using bis-15N-FU as internal standard. Intravenous injections of 2-14C-Ft and 2',5'-14C-Ft were given to rats and rabbits respectively, and plasma and urine were analyzed for Ft, and 14C activity. Unchanged Ft accounted for most of the 14C activity in plasma, while FU concentrations were below 0.15% and 0.4% relative to Ft concentrations in the rabbit and the rat, respectively. 30-60% of the urinary 14C activity was unchanged Ft and less than 0.2% FU. The significance or low FU levels is discussed in view of the hypothesis that Ft acts as a transport form of its metabolite FU.