TY - JOUR T1 - Investigation of the Quantitative Metabolic Fate and Urinary Excretion of 3-Methyl-4-Trifluoromethylaniline and 3-Methyl-4-Trifluoromethylacetanilide in the Rat JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1171 LP - 1178 VL - 27 IS - 10 AU - Graeme B. Scarfe AU - John C. Lindon AU - Jeremy K. Nicholson AU - Brian Wright AU - Eddie Clayton AU - Ian D. Wilson Y1 - 1999/10/01 UR - http://dmd.aspetjournals.org/content/27/10/1171.abstract N2 - The urinary metabolites of 3-methyl-4-trifluoromethylaniline in the rat were characterized and quantified using a combination of19F NMR, HPLC-NMR (1H and 19F), and HPLC-mass spectrometry techniques. The major routes of metabolism were amine N-acetylation and methyl groupC-oxidation to the benzyl alcohol (with subsequent glucuronide conjugation) and further to the corresponding benzoic acid derivative. Quantitatively only a small proportion of the urinary metabolites contained the free amino group, and these were products ofortho-hydroxylation (2 and 6 position) with additional conjugation to form the ether sulfates and glucuronides. AnN-glucuronide of the parent compound was also identified. 3-Methyl-4-trifluoromethylacetanilide (13C-labeled in the acetyl group) gave virtually the same overall metabolite profile as 3-methyl-4-trifluoromethylaniline; however, a significant level of futile N-deacetylation and reacetylation occurred as ca. 50% of the excretedN-acetylated major metabolites contained no13C-label at the acetyl, having been replaced by an endogenous 12C-acetyl source. This level of futile deacetylation is the highest yet reported for a substituted aniline/acetanilide and indicates a high degree of electronic activation of the amino group toward the acetyltransferase enzymes in vivo. The American Society for Pharmacology and Experimental Therapeutics ER -