H-1 AND F-19-NMR SPECTROSCOPIC STUDIES ON THE METABOLISM AND URINARY-EXCRETION OF MONOSUBSTITUTED AND DISUBSTITUTED PHENOLS IN THE RAT

1. H-1 and F-19-nmr spectroscopy was used to investigate quantitativel y the urinary excretion of the metabolites of 15 substituted phenols i n the rat. The compounds studied were: 2-, 3-, and 4-fluorophenols; 2- , 3-, and 4-trifluoromethylphenol; 2,4-, 2,6- and 3,4-difluorophenol; 2-fluoro-5-trifluoromethylphenol, 3-fluoro-5-trifluoromethylphenol, 2- trifluoromethyl-4-fluorophenol; 3-chloro-4-fluorophenol, 3-fluoro-4-ch lorophenol, and 3-methyl-4-fluorophenol. All compounds were dosed to t he Sprague-Dawley rat (10 mg/kg i.p.) and urine was collected over the periods 0-8, 8-24 and 24-48 h post-dosing and analyzed using nmr spec troscopy. 2. The compounds were excreted in the urine mainly as glucur onide or sulphate conjugates or as the unchanged parent compound. Ther e was considerable variation in the urinary excretion of the compounds over 48 h ranging from 22.1 to 93.6% of the dose. There was no appare nt relationship between the molecular weight of compounds or their met abolites and the percentage molar recovery of each in the urine. 3. Or tho-substituted phenols in general showed a greater propensity for glu curonidation than did either meta- or pava-substituted compounds, irre spective of the substituent group. The molar glucuronide-to-sulphate r atio for ortho-substituted compounds was found to be 2.2 +/- 0.9 where as the ratio for both meta- and pava-substituted compounds was 0.8 +/- 0.2 (p < 0.0001). 4. There were characteristic substituent effects of phenolic glucuronidation or sulphation on the F-19-nmr chemical shift s for both F- and CF3-substituted phemols and these substituent effect s were a useful aid to metabolite signal assignment. 5. These studies show that nmr spectroscopy provides a rapid and convenient approach to the construction of metabolic databases of simple xenobiotics for the investigation of structure-metabolism relationships.