Heteronuclear 19F-1H Statistical Total Correlation Spectroscopy as a Tool in Drug Metabolism: Study of Flucloxacillin Biotransformation

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• 作者：Hector C. Keun ; Toby J. Athersuch ; Olaf Beckonert ; Yulan Wang ; Jasmina Saric ; John P. Shockcor ; John C. Lindon ; Ian D. Wilson ; Elaine Holmes ; Jeremy K. Nicholson
• 刊名：Analytical Chemistry
• 出版年：2008
• 出版时间：February 15, 2008
• 年：2008
• 卷：80
• 期：4
• 页码：1073 - 1079
• 全文大小：457K
• 年卷期：v.80,no.4(February 15, 2008)
• ISSN：1520-6882

文摘

We present a novel application of the heteronuclearstatistical 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 to24 h after oral dosing with 500 mg of flucloxacillin. Avariety of statistical relationships between and within thespectroscopic datasets were explored without significantloss of the typically high 1D spectral resolution, generating¹H-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 ~0.8Hz/pt for both nuclei. The efficient statistical editingprovided by these methods readily allowed the collectionof drug metabolic data and assisted structure elucidation.This approach is of general applicability for studying themetabolism of other fluorine-containing drugs, includingimportant anticancer agents such as 5-fluorouracil andflutamide, and is extendable to any drug metabolism studywhere there is a spin-active X-nucleus (e.g., ¹³C, ¹⁵N, ³¹P)label present.