Fluorine nuclear magnetic resonance spectroscopy of human biofluids in the field of metabolic studies of anticancer and antifungal fluoropyrimidine drugs

doi:10.1016/j.cca.2005.10.013

Clinica Chimica Acta

Volume 366, Issues 1–2, April 2006, Pages 61-73

https://doi.org/10.1016/j.cca.2005.10.013 Get rights and content

Abstract

Fluorine-19 nuclear magnetic resonance (¹⁹F NMR) spectroscopy provides a highly specific tool for the detection, identification and quantification of fluorine-containing drugs and their metabolites in biofluids. The value and difficulties encountered in investigations on drug metabolism are first discussed. Then the metabolism of three fluoropyrimidines in clinical use, 5-fluorouracil, 5-fluorocytosine and capecitabine are reported. Besides the parent drug and the already known fluorinated metabolites, 12 new metabolites were identified for the first time with ¹⁹F NMR in human biofluids. Nine of them can only be observed with this technique: fluoride ion, N-carboxy-α-fluoro-β-alanine, α-fluoro-β-alanine conjugate with deoxycholic acid, 2-fluoro-3-hydroxypropanoic acid, fluoroacetic acid, O₂-β-glucuronide of fluorocytosine, fluoroacetaldehyde hydrate and its adduct with urea, fluoromalonic acid semi-aldehyde adducts with urea. This emphasizes the high analytical potential of ¹⁹F NMR for the furtherance in the understanding of fluoropyrimidine catabolic pathways. ¹⁹F NMR should also play a role in the therapeutic monitoring of FU and its prodrugs in specific groups of patients, e.g. hemodialyzed patients or patients with deficiency in FU catabolic enzymes.

Introduction

Nuclear Magnetic Resonance spectroscopy (NMR) is the study of molecules by recording the interaction of radiofrequency electromagnetic radiation with the magnetically active nuclei of molecules placed in a strong magnetic field. Modern NMR is the preeminent method for determining the structure of organic compounds including the three-dimensional structures of proteins and other biological macromolecules in solution. NMR is also widely used to determine the structures and characterize the solution chemistry of inorganic and organometallic compounds. But NMR has also found many applications in biomedical field since it allows the direct study at the molecular level of biological samples, from biofluids, cell or tissue extracts, excised tissues, cell pellets (in vitro studies) to isolated perfused biological systems (cells or organs) (ex vivo studies) and finally intact biological systems (bacteria, plants, animals and humans) (in vivo studies). Consequently, NMR is particularly well suited to analysis of the metabolism of both endogenous and xenobiotic compounds such as drugs.

Several active nuclei can be routinely used in drug metabolism and disposition such as proton, carbon-13, fluorine-19, phosphorus-31, lithium-7. Nevertheless, the majority of studies in the literature concerns fluorine-19 NMR (¹⁹F NMR). Indeed, this nucleus presents favorable NMR characteristics, including a nuclear spin of 1/2, relatively narrow lines, 100% natural abundance, high sensitivity (83% that of proton), large chemical shift range (about 500 ppm), and short longitudinal relaxation times (T₁) which permit rapid pulsing with a corresponding improvement in the signal-to-noise ratio per unit time. As a number of fluorinated drugs are currently in clinical use, ¹⁹F NMR offers a powerful method of monitoring their pharmacokinetics and metabolism either in vitro or in vivo.

This article will focus on the application of ¹⁹F NMR to metabolic studies of fluoropyrimidine (FP) drugs from human biofluid analysis, emphasizing the usefulness of the technique for the quantitative detection of novel and unexpected metabolites.

The advantages and limitations of NMR, especially ¹⁹F NMR, for drug metabolism studies in biofluids are first discussed. Then, we present the ¹⁹F NMR studies dealing with three FP in clinical use: the anticancer drug 5-fluorouracil (FU), the mainstay of antimetabolite treatment for solid tumors, the antifungal agent 5-fluorocytosine (FC) and the recent oral prodrug of FU, capecitabine (CAP), which is a fluorocytidine derivative.

Section snippets

Advantages and limitations of NMR biofluids analysis for drug metabolism studies

NMR has several significant advantages over conventional chromatographic and electrophoretic methods. It enables the direct study of any intact biofluid without prior treatment, avoiding the problems stemming from chemical derivatization and from the pH-sensitivity of many metabolites.

The method is non-selective and requires no prior knowledge of the structures of metabolites since all the molecules bearing the nucleus under investigation are simultaneous detected in a single analysis.

A NMR

Fluorouracil (FU)

Since its introduction in clinical use more than 45 years ago, FU has become a component of the standard therapy for a variety of malignancies including gastrointestinal tract, head and neck, and breast cancers [13]. FU is a prodrug that requires intracellular complex metabolic conversion to fluoronucleosides (FNUCs) and then to cytotoxic fluoronucleotides (FNUCt). Besides this biochemical activation pathway, called anabolism, there is a degradative pathway called catabolism that leads to the

Fluorocytosine (FC)

FC is an antifungal agent used for the treatment of severe fungal infections, particularly when combined to amphotericin B. The antifungal activity of FC results from the intrafungal formation of FU leading to the inhibition of RNA processing and DNA synthesis via FNUCt metabolites. Susceptible fungi contain cytosine deaminase (CD; E.C. 3.5.4.1), the enzyme that converts FC to FU, whereas human cells lack this enzyme thus creating a theoretical absence of toxicity for FC in humans. However,

Capecitabine (CAP)

N⁴-Pentyloxycarbonyl-5′-deoxy-5-fluorocytidine, more commonly called capecitabine (CAP) or Xeloda®, is a recent prodrug of 5′dFUR, another FU prodrug, that is administered orally to circumvent the unacceptable toxicity of 5′dFUR without compromising its antitumor efficacy [47]. Since the main limitation of 5′dFUR derives from its gastrointestinal toxicity (diarrhea) attributed to the liberation of FU in the small intestine under the action of thymidine phosphorylase (TP; E.C. 2.4.2.4) [48], CAP

Conclusion

Despite its limited sensitivity in the low micromolar range, ¹⁹F NMR is a high potential analytical technique for metabolic studies of FP such as FU, FC or CAP. For biofluid analysis, it can be considered as concurrent to, and even in some cases, more performing than chromatographic techniques.

Indeed, ¹⁹F NMR allowed to detect, identify and quantify:

–
10 new FU metabolites in biofluids of patients treated with this drug: F⁻, CFBAL, 3 FBAL conjugates with bile acids, FHPA and FAC as well as

References (62)

F. Malz et al.
Validation of quantitative NMR
J Pharm Biomed Anal
(2005)
G. Weckbecker
Biochemical pharmacology and analysis of fluoropyrimidine alone and in combination with modulators
Pharm Ther
(1991)
D.J.Y. Porter et al.
Enzymatic elimination of fluoride from α-fluoro-β-alanine
Biochem Pharmacol
(1995)
M. Kaneko et al.
Inhibition of D-3-aminoisobutyrate-pyruvate aminotransferase by 5-fluorouracil and α-fluoro-β-alanine
Biochim Biophys Acta
(1992)
D.A. Keller et al.
Fluoroacetate-mediated toxicity of fluorinated ethanes
Fundam Appl Toxicol
(1996)
M.R. Johnson et al.
Purification and characterization of bile acid-CoA:amino acid N-acyltransferase from human liver
J Biol Chem
(1991)
K.L. Mukherjee et al.
Studies on fluorinated pyrimidines: IX. The degradation of 5-fluorouracil-6-C¹⁴
J Biol Chem
(1960)
B.W. Manning et al.
Use of a semicontinuous culture system as a model for determining the role of human intestinal microflora in the metabolism of xenobiotics
J Microb Methods
(1987)
M. Miwa et al.
Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue
Eur J Cancer
(1998)
G.P. Stathopoulos et al.
Front-line treatment of inoperable or metastatic pancreatic cancer with gemcitabine and capecitabine: an intergroup, multicenter phase II study
Ann Oncol
(2004)

J.A. O'Shaughnessy et al.

Randomized open-label, phase II trial of oral capecitabine (Xeloda) vs. a reference arm of intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) as first-line therapy for advanced/metastatic breast cancer

Ann Oncol

(2001)

W.E. Hull

Measurement of absolute metabolite concentrations in biological samples

Bruker Rep

(1986)

J. Bernadou et al.

Complete urinary excretion profile of 5-fluorouracil during a six-day chemotherapy schedule by ¹⁹F nuclear magnetic resonance

Clin Chem

(1985)

M.C. Malet-Martino et al.

Evidence for the importance of 5′-deoxy-5-fluorouridine catabolism in humans from ¹⁹F nuclear magnetic resonance spectrometry

Cancer Res

(1986)

J.P. Vialaneix et al.

Direct detection of new fluorocytosine metabolites in human biofluids by ¹⁹F nuclear magnetic resonance

Drug Metab Dispos

(1987)

W.E. Hull et al.

Metabolites of 5-fluorouracil in plasma and urine as monitored by ¹⁹F nuclear magnetic resonance with or without methotrexate treatment

Cancer Res

(1988)

L. Lemaire et al.

Cardiotoxicity of commercial 5-fluorouracil vials stems from the alkaline hydrolysis of this drug

Br J Cancer

(1992)

M. Arellano et al.

5-Ethynyluracil (GW 776): effects on the formation of the toxic catabolites of 5-fluorouracil, fluoroacetate and fluorohydroxypropionic acid in the isolated perfused rat liver model

Br J Cancer

(1997)

F. Desmoulin et al.

Metabolism of capecitabine, an oral fluorouracil prodrug: ¹⁹F NMR studies in animal models and human urine

Drug Metab Dispos

(2002)

J. Rengelshausen et al.

Pharmacokinetics of 5-fluorouracil and its catabolites determined by ¹⁹F nuclear magnetic resonance spectroscopy for a patient on chronic hemodialysis

Am J Kidney Dis

(2002)

Y.J.L. Kamm et al.

Effect of modulators on 5-fluorouracil metabolite patterns in murine colon carcinoma determined by in vitro ¹⁹F nuclear magnetic resonance spectroscopy

Cancer Res

(1994)

Y.J.L. Kamm et al.

5-Fluorouracil metabolite patterns in viable and necrotic tumor areas of murine colon carcinoma determined by ¹⁹F NMR spectroscopy

Magn Reson Med

(1996)

G.J. Peters et al.

New antimetabolites in preclinical and clinical development

Expert Opin Invest Drugs

(1996)

R.B. Diasio et al.

Clinical pharmacology of 5-fluorouracil

Clin Pharm

(1989)

J.L. Grem

5-Fluoropyrimidines

R. Duschinsky et al.

(+)-α-Fluoro-β-alanine (FBAL), the main metabolite of 5-fluorouracil (FU) and its enantiomer

Proc Am Assoc Cancer Res

(1973)

D. Gani et al.

Stereochemistry of catabolism of the DNA base thymine and of the anti-cancer drug 5-fluorouracil

J Chem Soc Perkin Trans I

(1985)

R. Martino et al.

¹⁹F nuclear magnetic resonance analysis of the carbamate reaction of α-fluoro-β-alanine (FBAL), the major catabolite of fluoropyrimidines. Application to FBAL carbamate determination in body fluids of patients treated with 5′-deoxy-5-fluorouridine

Drug Metab Dispos

(1987)

R. Martino et al.

Release of fluoride ion from 5′-deoxy-5-fluorouridine, an antineoplastic fluoropyrimidine in humans

Drug Metab Dispos

(1985)

M. Arellano et al.

The anti-cancer drug 5-fluorouracil is metabolized by the isolated perfused rat liver and in rats into highly toxic fluoroacetate

Br J Cancer

(1998)

O.W. Griffith

β-Amino acids: mammalian metabolism and utility as α-amino acid analogues

Ann Rev Biochem

(1986)

Cited by (49)

Treatment technologies for removal of per- and polyfluoroalkyl substances (PFAS) in biosolids
2023, Chemical Engineering Journal
Citation Excerpt :
This results in the introduction of novel methods such as TF organic and inorganic analysis, which comprise absorbable organic fluorine (AOF), particle-induced gamma-ray emission (PIGE), and combustion ion chromatography (CIC). It is worth noting that techniques such as fluorine-19 nuclear magnetic resonance spectroscopy, X-ray photoelectron spectroscopy, and inductively coupled plasma-mass spectrometry has emerged to ensure fluorine/organic fluorine [158]. Table 3 discusses the merits and demerits of different PFAS analysis techniques.
PFAS (per- and polyfluoroalkyl substances) possess hydrophobic and hydrophilic characteristics, recalcitrant nature due to a strong C-F bond, and have the potential to endure adverse environmental situations and greater surface activity. Biosolids are the side-resultant in the sludge treatment process, which are primarily applied as soil conditioners. These PFAS have been detected at an abnormal level in biosolids and through various routes retained in the human and animal systems. However, for PFAS, in-depth consideration of physical and chemical properties and exposure pathways is still limited, ultimately curbing the development of new technologies which pave the trails for PFAS destruction. Several attempts have been carried out using the biological approach, and hydrolytic methods, but the carbon–fluorine bond being resistant to these approaches limits them. Therefore, impactful end-of-life technologies are required for PFAS remediation in biosolids. The current review provides new insights into PFAS destruction technologies. Different emerging PFAS destruction technologies such as incineration, hydrothermal liquefaction, pyrolysis, thermal hydrolysis, supercritical water oxidation, and several other processes, their latest advancements and limitations have been discussed in detail in this current study. Classification of PFAS, exposure of PFAS to the environment and human exposure, ways in which humans can avoid PFAS, and different detection techniques for PFAS analysis along with their merits and demerits have been broadly discussed in this review. The mechanism of PFAS degradation during thermal processes has also been covered.
Charge density distribution effect in pyrrolidine-fused chlorins on microbial uptake and antimicrobial photoinactivation of microbial pathogens
2021, Journal of Photochemistry and Photobiology B: Biology
Citation Excerpt :
This structural feature produces an increment of the amphiphilic character, which can be advantageous for the uptake of microbial cells. Moreover, PFP groups can also be used for 19F magnetic resonance imaging in combination with red fluorescence imaging of the chlorin macrocycle for biomedical investigations [40–42]. In addition, fluorinated porphyrinoids usually have higher photostability towards oxidative degradation than the corresponding unsubstituted fluorine analogs [15].
Two novels structurally related pyrrolidine-fused chlorins were synthesized from 5,10,15,20-tetrakis(pentafluorophenyl)chlorin by nucleophilic aromatic substitution of the para-fluoro groups. The reaction with 2-dimethylaminoethanol produced TPCF₁₆-NMe₂ in 77% yield, while TPCF₁₆-NBu was obtained using butylamine in 87% yield. The latter was extensively methylated to form TPCF₁₆-N⁺Bu in 92% yield. The synthetic strategy was designed to compare the effect of charge density distribution on chlorin in the efficacy to induce photodynamic inactivation of pathogens. TPCF₁₆-NMe₂ has five tertiary amines that can acquire positive charges in aqueous medium by protonation. Furthermore, four of the cationic groups are located in amino groups linked to the chlorine macrocycle by an aliphatic structure of two carbon atoms, which gives it greater movement capacity. In contrast, TPCF₁₆-N⁺Bu presents intrinsic positive charges on aromatic rings. Absorption and fluorescence emission properties were not affected by the peripheral substitution on the chlorin macrocycle. Both photosensitizers (PSs) were able to form singlet molecular oxygen and superoxide anion radical in solution. Uptake and photodynamic inactivation mediated by these chlorins were examined on Staphylococcus aureus and Escherichia coli. Both phototherapeutic agents produced efficient photoinactivation of S. aureus. However, only TPCF₁₆-NMe₂ was rapidly bound to E. coli cells and this chlorin was effective to photoinactivate both strains of bacteria using lower concentrations and shorter irradiation periods. Our outcomes reveal that the charge density distribution is a key factor to consider in the development of new PSs. Accordingly, this work stands out as a promising starting point for the design of new tetrapyrrolic macrocycles with application in PDI.
From medium to endoplasmic reticulum: Tracing anticancer phenolato titanium(IV) complex by <sup>19</sup>F NMR detection
2021, Journal of Inorganic Biochemistry
Citation Excerpt :
This can be achieved by preliminary calibration of the primary NMR parameters, such as relaxation time (T1), repetition time (D1), and 90° pulse, followed by conducting the measurements under specific conditions, such as uniform pulse excitation on spectral width and 1H decoupling during acquisition only [40–42]. Moreover, fluorinated compounds are rarely found naturally in biological systems; thus, 19F NMR provides an effective and distinctive method for cellular detection of fluorinated active species deriving from an administered drug [36,39,43–45]. Therefore, quantitative 19F NMR measurements played a significant role in the discovery of the metabolism, the cellular distribution, and the mechanism of action of various drugs, in both in-vitro and in-vivo studies [46–51].
Titanium(IV) complexes of diaminobis(phenolato)-bis(alkoxo) ligands are promising anticancer drugs, showing marked in-vivo efficacy with no toxic side-effects in mice, hence, it is of interest to elucidate their mechanism of action. Herein, we employed a fluoro-substituted derivative, FenolaTi, for mechanistic analysis of the active species and its cellular target by quantitative ¹⁹F NMR detection to reveal its biodistribution and reactivity in extracellular and intracellular matrices. Upon administration to the serum-containing medium, FenolaTi interacted with bovine serum albumin. 20 h post administration, the cellular accumulation of FenolaTi derivatives was estimated as 37% of the administered compound, in a concentration three orders-of-magnitude higher than the administered dose, implying that active membrane transportation facilitates cellular penetration. An additional 19% of the administered dose that was detected in the extracellular environment had originated from post-apoptotic cells. In the cell, interaction with cellular proteins was detected. Although some intact Ti(IV) complex localized in the nucleus, no signals for isolated DNA fractions were detected and no reactivity with nuclear proteins was observed. Interestingly, higher accumulation of FenolaTi-derived compounds in the endoplasmic reticulum (ER) and interaction with proteins therein were detected, supporting the role of the ER as a possible target for cytotoxic bis(phenolato)-bis(alkoxo) Ti(IV) complexes.
Protein-Inhibitor Interaction Studies Using NMR
2015, Applications of NMR Spectroscopy
Solution-state NMR has been widely applied to determine the three-dimensional structure, dynamics, and molecular interactions of proteins. The designs of experiments used in protein NMR differ from those used for small-molecule NMR, primarily because the information available prior to an experiment, such as molecular mass and knowledge of the primary structure, is unique for proteins compared to small molecules. In this review article, protein NMR for structural biology is introduced with comparisons to small-molecule NMR, such as descriptions of labeling strategies and the effects of molecular dynamics on relaxation. Next, applications for protein NMR are reviewed, especially practical aspects for protein-observed ligand-protein interaction studies. Overall, the following topics are described: (1) characteristics of protein NMR, (2) methods to detect protein-ligand interactions by NMR, and (3) practical aspects of carrying out protein-observed inhibitor-protein interaction studies.
Detection of <sup>19</sup>F-labeled biopharmaceuticals in cell cultures with magnetic resonance
2013, Advanced Drug Delivery Reviews
Magnetic resonance (MR) studies of the therapeutic efficacy of fluorinated drugs have recently become possible due to improvements in detection including the application of very strong magnetic fields up to 9.4 Tesla (T). These advances allow tracking, identification, and quantification of ¹⁹F-labeled biopharmaceuticals using ¹⁹F MR imaging (¹⁹F MRI) and spectroscopy (¹⁹F MRS). Both techniques are noninvasive, are nondestructive, and enable serial measurements. They also allow for controlled and systematic studies of cellular metabolism in cancerous tissue in vivo (small animals and humans) and in vitro (body fluids, cells culture, tissue extracts and isolated tissues). Here we provide an overview of the ¹⁹F MRI and ¹⁹F MRS techniques used for tracking ¹⁹F labeled anticancer chemotherapeutics and antibodies which allow quantification of drug uptake in cancer cells in vitro.
Fluorine detected 2D NMR experiments for the practical determination of size and sign of homonuclear F-F and heteronuclear C-F multiple bond J-coupling constants in multiple fluorinated compounds
2013, Journal of Magnetic Resonance
Citation Excerpt :
In this field, fluorine is present in 54% of the herbicides/safeners, 27% of the insecticides/acaricides, and 19% of the fungicides on the market [9]. Recent developments in fluoro-chemistry, besides the potentially biodegradable fluoro-analogs of DDT, that possess even greater insecticidal and pesticidal activities [10], comprise the use of fluorine in high-throughput screening, binding and biochemical assays [11–14], in metabolic studies [15] as well as the use of fluorine labeled contrast or tracer agents for in vivo 19F MRI [16–18]. The widespread usage will – according to our expectation – further expand the significance of fluorine in life sciences and thus the need for more and better experiments for characterization.
The use of fluorine in molecules obtained from chemical synthesis has become increasingly important within the pharmaceutical and agricultural industry. NMR characterization of these compounds is of great value with respect to their structure elucidation, their screening in metabolomics investigations and binding studies. The favorable NMR properties of the fluorine nucleus make NMR with fluorine detection of great value in this respect. A suite of NMR 2D F–F- and F–C-correlation experiments with fluorine detection was applied to the assignment of resonances, ⁿJ_CF- and ⁿJ_FF-couplings as well as the determination of their size and sign. The utilization of this experiment suite was exemplarily demonstrated for a highly fluorinated vinyl alkyl ether. Especially F–C HSQC and J-scaled F–C HMBC experiments allowed determining the size of the J-couplings of this compound. The relative sign of its homo- and heteronuclear couplings was achieved by different combinations of 2D NMR experiments, including non-selective and F2-selective F–C XLOC, F2-selective F–C HMQC, and F–F COSY. The F2-one/two-site selective F–C XLOC versions were found highly useful, as they led to simplifications of the common E.COSY patterns and resulted in a higher confidence level of the assignment by using selective excitation. The combination of F2-one/two-site selective F–C XLOC experiments with a F2-one-site selective F–C HMQC experiment provided the signs of all ⁿJ_CF- and ⁿJ_FF-couplings in the vinyl moiety of the test compound. Other combinations of experiments were found useful as well for special purposes when focusing for example on homonuclear couplings a combination of F–F COSY-10 with a F2-one-site selective F–C HMQC could be used. The E.COSY patterns in the spectra demonstrated were analyzed by use of the spin-selective displacement vectors, and in case of the XLOC also by use of the DQ- and ZQ-displacement vectors. The variety of experiments presented shall contribute to facilitate the interpretation of F–C correlations as well as to open alternative pathways for the determination of size and signs of homo- and heteronuclear couplings of multiply fluorinated small molecules.

View all citing articles on Scopus

View full text

ReviewFluorine nuclear magnetic resonance spectroscopy of human biofluids in the field of metabolic studies of anticancer and antifungal fluoropyrimidine drugs

Abstract

Introduction

Section snippets

Advantages and limitations of NMR biofluids analysis for drug metabolism studies

Fluorouracil (FU)

Fluorocytosine (FC)

Capecitabine (CAP)

Conclusion

J Pharm Biomed Anal

Pharm Ther

Biochem Pharmacol

Biochim Biophys Acta

Fundam Appl Toxicol

J Biol Chem

J Biol Chem

J Microb Methods

Eur J Cancer

Ann Oncol

Ann Oncol

Measurement of absolute metabolite concentrations in biological samples

Bruker Rep

Complete urinary excretion profile of 5-fluorouracil during a six-day chemotherapy schedule by 19F nuclear magnetic resonance

Clin Chem

Evidence for the importance of 5′-deoxy-5-fluorouridine catabolism in humans from 19F nuclear magnetic resonance spectrometry

Cancer Res

Direct detection of new fluorocytosine metabolites in human biofluids by 19F nuclear magnetic resonance

Drug Metab Dispos

Metabolites of 5-fluorouracil in plasma and urine as monitored by 19F nuclear magnetic resonance with or without methotrexate treatment

Cancer Res

Cardiotoxicity of commercial 5-fluorouracil vials stems from the alkaline hydrolysis of this drug

Br J Cancer

5-Ethynyluracil (GW 776): effects on the formation of the toxic catabolites of 5-fluorouracil, fluoroacetate and fluorohydroxypropionic acid in the isolated perfused rat liver model

Br J Cancer

Metabolism of capecitabine, an oral fluorouracil prodrug: 19F NMR studies in animal models and human urine

Drug Metab Dispos

Pharmacokinetics of 5-fluorouracil and its catabolites determined by 19F nuclear magnetic resonance spectroscopy for a patient on chronic hemodialysis

Am J Kidney Dis

Effect of modulators on 5-fluorouracil metabolite patterns in murine colon carcinoma determined by in vitro 19F nuclear magnetic resonance spectroscopy

Cancer Res

5-Fluorouracil metabolite patterns in viable and necrotic tumor areas of murine colon carcinoma determined by 19F NMR spectroscopy

Magn Reson Med

New antimetabolites in preclinical and clinical development

Expert Opin Invest Drugs

Clinical pharmacology of 5-fluorouracil

Clin Pharm

5-Fluoropyrimidines

(+)-α-Fluoro-β-alanine (FBAL), the main metabolite of 5-fluorouracil (FU) and its enantiomer

Proc Am Assoc Cancer Res

Stereochemistry of catabolism of the DNA base thymine and of the anti-cancer drug 5-fluorouracil

J Chem Soc Perkin Trans I

19F nuclear magnetic resonance analysis of the carbamate reaction of α-fluoro-β-alanine (FBAL), the major catabolite of fluoropyrimidines. Application to FBAL carbamate determination in body fluids of patients treated with 5′-deoxy-5-fluorouridine

Drug Metab Dispos

Release of fluoride ion from 5′-deoxy-5-fluorouridine, an antineoplastic fluoropyrimidine in humans

Drug Metab Dispos

The anti-cancer drug 5-fluorouracil is metabolized by the isolated perfused rat liver and in rats into highly toxic fluoroacetate

Br J Cancer

β-Amino acids: mammalian metabolism and utility as α-amino acid analogues

Ann Rev Biochem

Review
Fluorine nuclear magnetic resonance spectroscopy of human biofluids in the field of metabolic studies of anticancer and antifungal fluoropyrimidine drugs

Complete urinary excretion profile of 5-fluorouracil during a six-day chemotherapy schedule by ¹⁹F nuclear magnetic resonance

Evidence for the importance of 5′-deoxy-5-fluorouridine catabolism in humans from ¹⁹F nuclear magnetic resonance spectrometry

Direct detection of new fluorocytosine metabolites in human biofluids by ¹⁹F nuclear magnetic resonance

Metabolites of 5-fluorouracil in plasma and urine as monitored by ¹⁹F nuclear magnetic resonance with or without methotrexate treatment

Metabolism of capecitabine, an oral fluorouracil prodrug: ¹⁹F NMR studies in animal models and human urine

Pharmacokinetics of 5-fluorouracil and its catabolites determined by ¹⁹F nuclear magnetic resonance spectroscopy for a patient on chronic hemodialysis

Effect of modulators on 5-fluorouracil metabolite patterns in murine colon carcinoma determined by in vitro ¹⁹F nuclear magnetic resonance spectroscopy

5-Fluorouracil metabolite patterns in viable and necrotic tumor areas of murine colon carcinoma determined by ¹⁹F NMR spectroscopy

¹⁹F nuclear magnetic resonance analysis of the carbamate reaction of α-fluoro-β-alanine (FBAL), the major catabolite of fluoropyrimidines. Application to FBAL carbamate determination in body fluids of patients treated with 5′-deoxy-5-fluorouridine