title: Heteronuclear 19F-1H statistical total correlation spectroscopy as a tool in drug metabolism: study of flucloxacillin biotransformation.
abstract: 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.
authors.affiliation: Department of Biomolecular Medicine, Division of Surgery, Oncology, Reproductive Biology and Anaesthetics, Faculty of Medicine, Imperial College London, South Kensington Campus, London SW7 2AZ, U.K. h.keun@imperial.ac.uk
authors.forename: Hector C
authors.initials: HC
authors.lastname: Keun
authors.forename: Toby J
authors.initials: TJ
authors.lastname: Athersuch
authors.forename: Olaf
authors.initials: O
authors.lastname: Beckonert
authors.forename: Yulan
authors.initials: Y
authors.lastname: Wang
authors.forename: Jasmina
authors.initials: J
authors.lastname: Saric
authors.forename: John P
authors.initials: JP
authors.lastname: Shockcor
authors.forename: John C
authors.initials: JC
authors.lastname: Lindon
authors.forename: Ian D
authors.initials: ID
authors.lastname: Wilson
authors.forename: Elaine
authors.initials: E
authors.lastname: Holmes
authors.forename: Jeremy K
authors.initials: JK
authors.lastname: Nicholson
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics* / Q000652:urine; D001711:Biotransformation; D005436:Floxacillin / Q000493:pharmacokinetics* / Q000652:urine; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D005472:Fluorouracil / Q000494:pharmacology / Q000652:urine; D005485:Flutamide / Q000493:pharmacokinetics / Q000652:urine; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D013223:Statistics as Topic; D013997:Time Factors
chemical_list: D000903:Antibiotics, Antineoplastic; D005462:Fluorine Radioisotopes; D005436:Floxacillin; D005485:Flutamide; D005472:Fluorouracil