Application of fluorine-19 nuclear magnetic resonance to the determination of plasma-protein binding of 5′-deoxy-5-fluorouridine, a new antineoplastic fluoropyrimidine

Meynial, D.; Lopez, André; Malet‐Martino, M. C.; Hoffmann, Jean-Sébastien; Martino, Robert

doi:10.1016/0731-7085(88)80029-3

Cited by 6 publications

(1 citation statement)

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“…19F NMR was also used to directly measure the percentage of5'dFUrd binding to plasma proteins, since two distinct signals corresponding to free and plasma proteinbound 5'dFUrd were observed in the plasma of patients treated with this drug (Malet- Martino et al 1986;Meynial et al 1988). A broadening of the fluorouracil signal or the occasional detection of 2 signals, one very broad, in the plasma of patients treated with fluorouracil also indicated a binding of this compound to plasma proteins (Hull et al 1988).…”

Section: Human Biofluid Studiesmentioning

confidence: 99%

Uses and Limitations of Nuclear Magnetic Resonance (NMR) Spectroscopy in Clinical Pharmacokinetics

Malet‐Martino

Martino

1991

Clinical Pharmacokinetics

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Biological nuclear magnetic resonance (NMR) spectroscopy has progressed rapidly in recent years since it is the sole analytical technique that permits the study, at the molecular level, of intact biological samples (biological fluids, cells, tissues, isolated perfused organs), animals and even humans. It is a noninvasive and nondestructive method that allows the simultaneous measurement of several endogenous or exogenous compounds. It also provides structural information on the observed metabolites, and changes in metabolic reactions as a function of time can be monitored. NMR is therefore an analytical technique particularly well suited to the studies of endogenous or xenobiotic metabolism.Several magnetically active nuclei are (or could be) used in NMR studies of the clinical pharmacokinetics of drugs. First of all, the 1 H nucleus is present in all drugs and has the highest NMR sensitivity of any stable nucleus. Moreover, it is the most abundant (99.98% natural abundance) of the 2 natural isotopes (IH and 2H or deuterium) of the hydrogen atom (table I). However, the small chemical shift range and the extensive multiplicity due to homonuclear j-coupling sometimes make the observation and quantification of drug metabolites difficult. Moreover, 1 H NMR spectra of biological fluids or tissues contain many intense resonances from water, proteins and lipids that must be reduced or eliminated.Two other useful NMR probes could be 13C and 15N. However, due to the low natural abundance and the low sensitivity of these isotopes (table I), and the generally low concentrations of drugs (and/ or metabolites) in biological systems, I3C or 15N NMR spectroscopy has not to date been applied to drug metabolism studies in humans. Improved sensitivity can be attained with polarisation transfer experiments which partly transfer the favourable properties of the proton to I3C or 15N. Further, I3C_ or 15N-enriched drugs can be synthesised in order to increase the NMR sensitivity. However, to obtain a full picture of the chemical changes taking place, the labelling of several key positions is desirable. This may be chemically difficult, presupposes an a priori knowledge of the metabolism of the particular drug and is very expensive in practice. 31 P NMR spectroscopy is widely used for intracellular pH measurements and in vivo metabolism studies since the signals are easily detected. However, few phosphorus-containing drugs are used in therapeutics, and the number of drug metabolism studies using 31 P NMR is therefore limited.7Li, the major lithium isotope, has a high NMR sensitivity. Unlike the other nuclei referred to in this article, 7Li is not a spin I = 1/2 but a spin I = 3/2 nucleus (table I). This isotope therefore possesses a quadrupole moment which gives rise to broad spectral lines. 7Li NMR is not hampered by interference with endogenous signals but, of course, it is restricted to the determination of the pharmacokinetic profile of lithium salts.

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Section: Human Biofluid Studiesmentioning

confidence: 99%