Simultaneous determination of 5-fluorouracil and its active metabolites in serum and tissue by high-performance liquid chromatography

Jung, Min Su; Berger, G.; Pohlen, U.; Päuser, S.; Reszka, Regina; Buhr, H. J.

doi:10.1016/s0378-4347(97)00368-x

Cited by 21 publications

(13 citation statements)

References 16 publications

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“…Jung et al (1997) detected an LOQ of 5-Fu similar to our data but different for 5-Furd and 5-Fdurd, as did Del Nozal et al (1992). Furthermore, in an in vitro study Cohen et al (1974) observed a minimum concentration required for cytotoxicity effect on cancer cells of the order of mg/mL.…”

Section: Discussionsupporting

confidence: 87%

“…Many authors proposed correlating toxicity with the expression of the main catabolic enzyme dihydropyrimidine dehydrogenase (DPD); (Gamelin et al, 1997a, although with controversial results, or evaluating the plasma levels of metabolites 5-fluorouridine (5-Furd), 5-fluoro-2'-deoxyuridine (5-Fdurd) and 5-fluoro-5,6-dihydro-uracil (5-FuH 2 ; Del Nozal et al, 1994a;Ackland et al, 1997;Jung et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

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Simultaneous HPLC determination of 5‐fluorouracil and its metabolites in plasma of cancer patients

Casale

Canaparo

Muntoni

et al. 2002

Biomedical Chromatography

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5-Fluorouracil (5-Fu) is a commonly used anticancer agent for treatment of solid tumours. Certain studies have reported conflicting results between individual plasma concentration levels and toxicity or therapeutic effects. For this reasons some authors proposed to evaluate the plasma levels of 5-Fu metabolites 5-fluorouridine, 5-fluoro-2'-deoxyuridine and 5-fluoro-5,6-dihydro-uracil. The aim of the present work is to develop and validate a new HPLC method simultaneously determining 5-fluorouracil and its three metabolites, to be used to study the plasma levels, therapeutic effects and toxicity in cancer patients. The analytes were separated on a 4.6 x 250 mm ODS1 (5 micro m) not end-capped column, operating at room temperature. Elution was performed under isocratic conditions, employing a 1.5 mM K(3)PO(4) mobile phase (pH 5). 5-Bromo-5,6-dihydro-uracil was used as internal standard. The limits of quantitation were 0.5 micro g/mL for 5-fluorouracil, 1 micro g/mL for 5-fluoro-5,6-dihydro-uracil, 3 micro g/mL for 5-fluoro-2'-deoxyuridine and 5-fluorouridine; the stability, recovery, linearity, accuracy and specificity of the compounds were evaluated according to the criteria widely accepted. Using this method we measured plasma samples of 18 cancer patients treated with folinic acid (100 mg/m(2)) by intravenous administration, followed by an i.v. bolus of 5-Fu (400 mg/m(2)). The concentration levels of 5-fluorouracil and for 5-fluoro-5,6-dihydro-uracil were detectable in all the subjects while 5-fluorouridine and 5-fluoro-2'-deoxyuridine were present only in eight patients.

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Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Simultaneous HPLC determination of 5‐fluorouracil and its metabolites in plasma of cancer patients

Casale

Canaparo

Muntoni

et al. 2002

Biomedical Chromatography

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“…Ultraviolet wavelength was 205 nm. The flow-rate was 1 mL/min [11,12] . The ratio of the peak area of 5-Fu to that of internal standard was plotted versus the concentration of the 5-Fu.…”

Section: Concentration-time Course Of 5-fu-gcl In Livermentioning

confidence: 99%

Pharmacokinetics and tissue distribution of 5-fluorouracil encapsulated by galactosylceramide liposomes in mice1

Jin

Longfu

et al. 2005

Acta Pharmacologica Sinica

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Aim: To study the pharmacokinetics and tissue distribution of 5‐fluorouracil encapsulated by galactosylceramide liposomes (5‐Fu‐GCL) in mice. Methods: The concentration of 5‐fluorouracil (5‐Fu) in serum was detected by high performance liquid chromatography after 5‐Fu‐GCL (80, 40, 20 mg/kg) and free 5‐Fu (40 mg/kg) were injected intravenously into mice. The tissue distribution of 5‐Fu‐GCL (40 mg/kg) and free 5‐Fu (40 mg/kg) was investigated, and concentration‐time profile of the two preparations in the liver were studied. Data were analyzed by 3p97 program. Results: Serum concentration‐time curves of 5‐Fu‐GCL and free 5‐Fu conformed to one compartment model of first order absorption. 5‐Fu‐GCL at 80, 40, and 20 mg/kg had T1/2Ke of 25.8±4.2, 27.3±4.4, and 28.2±5.6 min; C0 of 24.9±4.9, 17.7±3.6, and 11.5±2.7 mg/L; and AUC of 990.0±45.2, 622.5±38.3, and 340.4±25.6 mg·min·L‐1, respectively. In contrast free 5‐Fu at 40 kg/mg had T1/2Ke of 15.8±2.2 min, C0 of 35.8±6.2 mg/L, AUC of 639.0±35.9 mg·min·L‐1. The tissue distribution of 5‐Fu‐GCL in the liver and immune organs was significantly increased, while in heart and kidney it was remarkably decreased. The AUC of 5‐Fu‐GCL in the liver was 3 times higher than that of free 5‐Fu. Conclusion: The pharmacokinetics and tissue distribution of 5‐Fu‐GCL appears to be linear‐related and dose‐dependent, and exhibits sustained‐release and hepatic target characteristics.

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“…A new procedure was established to determine the 5-FU and 5-FUrd concentrations in the various organs [32]. The blood was centrifuged to obtain serum and the individual organs (tumor, liver, spleen, kidneys, stomach, pancreas, peritoneum and lymph nodes) were homogenized for 1 min without buffer in an ice-cooled beaker.…”

Section: Determination Of 5-fu and 5-furd Concentrations By Hplcmentioning

confidence: 99%

Intra-Aortal Therapy with 5-Fluorouracil- Polyethylene Glycol Stealth Liposomes: Does the Metabolism of 5-Fluorouracil into 5-Fluoro-2′-Deoxyuridine Depend on pH Value?

Pohlen

Binnenhei²,

Reszka³

et al. 2004

Chemotherapy

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Background: The application of liposome-encapsulated cytostatics results in higher concentrations in tumor tissue. This effect can be further increased by blood flow retardation with longer retention time in the tumor and by arterial administration realized in abdominal stop-flow therapy, a separate partial circulation with a defined flow under hypoxic conditions. The pH changes under stop-flow therapy may affect the further metabolism of 5-fluorouracil (5-FU), used here. Methods: The in vitro 5-fluoro-2′-deoxyuridine (5-FUrd) concentrations at increasing pH values were measured using liposomal encapsulated and free 5-FU. Subsequently, 20 chinchilla rabbits were treated intra-aortally with 5-FU or 5-FU-polyethylene glycol (PEG) liposomes. The pH value was maintained in the physiological range by continuous NaHCO₃ application. After 20 min, concentrations of 5-FU and its metabolite 5-FUrd were determined in different organs, the perfusate, serum and the VX-2 tumor by HPLC. Results: The in vitro 5-FUrd concentrations, which occur only in the physiological pH range, were doubled by the use of 5-FU-PEG liposomes. In the animal trial, NaHCO₃ titration doubled the 5-FUrd concentrations found in our preliminary studies. Compared to free 5-FU, 5-FU-PEG liposomes significantly increased the concentrations in the VX-2 liver tumor by 6.6-fold and in the para-aortal lymph nodes by 8.76-fold. Conclusion: The metabolism of 5-FU into its active metabolite 5-FUrd depends on the pH value and can be modulated. 5-FUrd concentrations can be approximately doubled with the intra-aortal application of 5-FU-PEG liposomes compared to free 5-FU.

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Simultaneous determination of 5-fluorouracil and its active metabolites in serum and tissue by high-performance liquid chromatography

Cited by 21 publications

References 16 publications

Simultaneous HPLC determination of 5‐fluorouracil and its metabolites in plasma of cancer patients

Simultaneous HPLC determination of 5‐fluorouracil and its metabolites in plasma of cancer patients

Pharmacokinetics and tissue distribution of 5-fluorouracil encapsulated by galactosylceramide liposomes in mice1

Intra-Aortal Therapy with 5-Fluorouracil- Polyethylene Glycol Stealth Liposomes: Does the Metabolism of 5-Fluorouracil into 5-Fluoro-2′-Deoxyuridine Depend on pH Value?

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