Metabolism of Capecitabine, an Oral Fluorouracil Prodrug:<sup>19</sup>F NMR Studies in Animal Models and Human Urine

Desmoulin, Franck; Gilard, Véronique; Malet‐Martino, Myriam; Martino, Robert

doi:10.1124/dmd.30.11.1221

Cited by 77 publications

(36 citation statements)

References 31 publications

(40 reference statements)

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“…(N 4 -pentoxycarbonyl-5′-deoxy-5-fl uorocytidine, Xeloda®), is an anticancer prodrug that was designed to undergo conversion in liver and tumors to 5-fl uorouracil (5-FU) (Guichard et al, 2005;Malet-Martino and Martino, 2002;Desmoulin et al, 2002;Judson et al, 1999).…”

Section: Capecitabinementioning

confidence: 98%

“…1, bio-activation of capecitabine to 5-FU is considered to take place in three steps by three diff erent enzymes Desmoulin et al, 2002;Zufi a et al, 2004;Judson et al, 1999;Ninomiya et al, 1990;Tabata et al, 2004). First, capecitabine is hydrolyzed to its fi rst metabolite 5′-deoxy-5-fl uorocytidine (5′-DFCR) by carboxylesterase, which is mainly present in liver and intestine.…”

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confidence: 99%

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A new, validated HPLC‐MS/MS method for the simultaneous determination of the anti‐cancer agent capecitabine and its metabolites: 5′‐deoxy‐5‐fluorocytidine, 5′‐deoxy‐5‐fluorouridine, 5‐fluorouracil and 5‐fluorodihydrouracil, in human plasma

Vainchtein

Rosing

Schellens

et al. 2009

Biomedical Chromatography

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A rapid and selective liquid chromatography/tandem mass spectrometric method was developed for the simultaneous determination of capecitabine and its metabolites 5'-deoxy-5-fluorocytidine (5'-DFCR), 5'-deoxy-5-fluorouracil (5'-DFUR), 5-fluorouracil (5-FU) and dihydro-5-fluorouracil (FUH(2)) in human plasma. A 200 microL human plasma aliquot was spiked with a mixture of internal standards fludarabine and 5-chlorouracil. A single-step protein precipitation method was employed using 10% (v/v) trichloroacetic acid in water to separate analytes from bio-matrices. Volumes of 20 microL of the supernatant were directly injected onto the HPLC system. Separation was achieved on a 30 x 2.1 mm Hypercarb (porous graphitic carbon) column using a gradient by mixing 10 mm ammonium acetate and acetonitrile-2-propanol-tetrahydrofuran (1 : 3 : 2.25, v/v/v). The detection was performed using a Finnigan TSQ Quantum Ultra equipped with the electrospray ion source operated in positive and negative mode. The assay quantifies a range from 10 to 1000 ng/mL for capecitabine, from 10 to 5000 ng/mL for 5'-DFCR and 5'-DFUR, and from 50 to 5000 ng/mL for 5-FU and FUH(2) using a plasma sample of 200 microL. Correlation coefficients (r(2)) of the calibration curves in human plasma were better than 0.99 for all compounds. At all concentration levels, deviations of measured concentrations from nominal concentration were between -4.41 and 3.65% with CV values less than 12.0% for capecitabine, between -7.00 and 6.59% with CV values less than 13.0 for 5'-DFUR, between -3.25 and 4.11% with CV values less than 9.34% for 5'-DFCR, between -5.54 and 5.91% with CV values less than 9.69% for 5-FU and between -4.26 and 6.86% with CV values less than 14.9% for FUH(2). The described method was successfully applied for the evaluation of the pharmacokinetic profile of capecitabine and its metabolites in plasma of treated cancer patients.

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Section: Capecitabinementioning

confidence: 98%

mentioning

confidence: 99%

A new, validated HPLC‐MS/MS method for the simultaneous determination of the anti‐cancer agent capecitabine and its metabolites: 5′‐deoxy‐5‐fluorocytidine, 5′‐deoxy‐5‐fluorouridine, 5‐fluorouracil and 5‐fluorodihydrouracil, in human plasma

Vainchtein

Rosing

Schellens

et al. 2009

Biomedical Chromatography

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“…In the current study, the <100% recovery of zebularine-and uridinerelated radioactivity in urine is due to the 2-position of the 14 C label in these compounds. When the 6-position of the pyrimidine ring is used for labeling or when the fluorine is traced by nuclear magnetic resonance, recovery of pyrimidinerelated material in urine is nearly complete (27,28). However, because labeling of pyrimidine analogues in the 2-position results in substantial loss of the 14 C label as 14 CO 2 through expiration, the remaining portion of the structure cannot be traced after that.…”

Section: Discussionmentioning

confidence: 99%

A Mass Balance and Disposition Study of the DNA Methyltransferase Inhibitor Zebularine (NSC 309132) and Three of Its Metabolites in Mice

Beumer

Joseph

Egorin

et al. 2006

Clinical Cancer Research

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Purpose:To elucidate the in vivo metabolic fate of zebularine (NSC 309132), a DNA methyltransferase inhibitor proposed for clinical evaluation in the treatment of cancer. Experimental Design: Male, CD 2 F 1 mice were dosed i.v. with 100 mg/kg 2-[ 14 C]zebularine. At specified times between 5 and 1,440 minutes, mice were euthanized. Plasma, organs, carcass, urine, and feces were collected and assayed for total radioactivity. Plasma and urine were also analyzed for zebularine and its metabolites with a previously validated high-pressure liquid chromatography assay. A similar experiment was done with 2-[ 14 C]uridine, the proposed primary metabolite of zebularine. Results: Maximum plasma concentrations were 462, 306, 33.6, 21.7, and 11.5 Amol/L for total radioactivity, zebularine, uridine, uracil (each at 5 minutes), and dihydrouracil (at 15 minutes), respectively. Total radioactivity, zebularine, uridine, uracil, and dihydrouracil were rapidly eliminated from plasma, and after 45 minutes, none of the individual compounds could be quantitated by high-pressure liquid chromatography. Plasma data were consistent with sequential conversion of zebularine to uridine, uracil, and dihydrouracil. 2-Pyrimidinone was not observed. Prolonged retention of radioactivity, at concentrations higher than in plasma, was observed in tissues. Recovery of given radioactivity in urine (30.3% of dose), feces (0.4% of dose), cage wash (7.9% of dose), and tissues and carcass (6.1% of dose) after 24 hours implied that up to 55% of radioactivity was expired as 14 CO 2 . Comparison of zebularine and uridine pharmacokinetic data indicated that f40% of the zebularine dose was converted to uridine. Conclusions: Zebularine is extensively and rapidly metabolized into endogenous compounds that are unlikely to have effects at the concentrations observed.

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“…shows major end products of metabolic pathway of CPC. 15 As the oncologists cite, intracellular anabolism of 5-fluorouracil (5-FU) is very complex. The formed complex named 5-fluorouridine-5'-triphosphate (5-FUTP) can be incorporated into RNA instead of uridine-5'-triphosphate (UTP), while the complex named 5-fluoro-2'-deoxyuridine-5'-triphosphate (5-FdUTP) can be incorporated into DNA because it acts as a substrate for DNA polymerases.…”

Section: Introductionmentioning

confidence: 99%

"SYNTHESIS AND SPECTRAL CHARACTERIZATION OF Fe(II) AND Mn(II) COMPLEXES WITH ORAL FLUOROURACIL PRO-DRUG CAPECITABINE "

2017

RJC

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Malignant neoplasms are today one of the leading causes of death in the world. Their treatment is extremely complex and requires the application of various chemical compounds which leads to disruption of homeostasis in the human body. During a treatment, there is a possibility of complex formation with important bioelements, such as copper, iron, cobalt, manganese, and others in the biological system. This paper presents the results of possible formation of complexes between Fe(II) and Mn(II) ions and capecitabine (IUPAC name: pentyl 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-methyl-tetra-hydrofuran-2-yl)-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl carbamate). This chemotherapeutic agent is often used for the treatment of different solid tumors including breast, colon, prostate, liver and gastrointestinal tract carcinoma. Spectroscopic methods (UV/Vis and FT-IR spectroscopy) were used in order to research specific compounds between CPC and metal ions that may be formed in human body under physiological and approximately physiological conditions. In addition, microscopic characterization and comparison of solid samples of capecitabine and products of interactions of CPC as a ligand with Fe(II) and Mn(II) ions have been performed. FT-IR spectra indicate the existence of interaction of these two divalent bio cations with CPC, i.e. their coordination through nitrogen and oxygen atoms of CPC. When UV spectra of pure ligand and model systems M(II)-CPC were compared, similar absorption bands were observed with absorption maxima at the same wavenumbers but lower absorbance values for model systems M(II)-CPC.

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Metabolism of Capecitabine, an Oral Fluorouracil Prodrug:¹⁹F NMR Studies in Animal Models and Human Urine

Cited by 77 publications

References 31 publications

A new, validated HPLC‐MS/MS method for the simultaneous determination of the anti‐cancer agent capecitabine and its metabolites: 5′‐deoxy‐5‐fluorocytidine, 5′‐deoxy‐5‐fluorouridine, 5‐fluorouracil and 5‐fluorodihydrouracil, in human plasma

A new, validated HPLC‐MS/MS method for the simultaneous determination of the anti‐cancer agent capecitabine and its metabolites: 5′‐deoxy‐5‐fluorocytidine, 5′‐deoxy‐5‐fluorouridine, 5‐fluorouracil and 5‐fluorodihydrouracil, in human plasma

A Mass Balance and Disposition Study of the DNA Methyltransferase Inhibitor Zebularine (NSC 309132) and Three of Its Metabolites in Mice

"SYNTHESIS AND SPECTRAL CHARACTERIZATION OF Fe(II) AND Mn(II) COMPLEXES WITH ORAL FLUOROURACIL PRO-DRUG CAPECITABINE "

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Metabolism of Capecitabine, an Oral Fluorouracil Prodrug:19F NMR Studies in Animal Models and Human Urine

Cited by 77 publications

References 31 publications

A new, validated HPLC‐MS/MS method for the simultaneous determination of the anti‐cancer agent capecitabine and its metabolites: 5′‐deoxy‐5‐fluorocytidine, 5′‐deoxy‐5‐fluorouridine, 5‐fluorouracil and 5‐fluorodihydrouracil, in human plasma

A new, validated HPLC‐MS/MS method for the simultaneous determination of the anti‐cancer agent capecitabine and its metabolites: 5′‐deoxy‐5‐fluorocytidine, 5′‐deoxy‐5‐fluorouridine, 5‐fluorouracil and 5‐fluorodihydrouracil, in human plasma

A Mass Balance and Disposition Study of the DNA Methyltransferase Inhibitor Zebularine (NSC 309132) and Three of Its Metabolites in Mice

"SYNTHESIS AND SPECTRAL CHARACTERIZATION OF Fe(II) AND Mn(II) COMPLEXES WITH ORAL FLUOROURACIL PRO-DRUG CAPECITABINE "

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Metabolism of Capecitabine, an Oral Fluorouracil Prodrug:¹⁹F NMR Studies in Animal Models and Human Urine