title: Investigation of the quantitative metabolic fate and urinary excretion of 3-methyl-4-trifluoromethylaniline and 3-methyl-4-trifluoromethylacetanilide in the rat.
abstract: The urinary metabolites of 3-methyl-4-trifluoromethylaniline in the rat were characterized and quantified using a combination of (19)F NMR, HPLC-NMR ((1)H and (19)F), and HPLC-mass spectrometry techniques. The major routes of metabolism were amine N-acetylation and methyl group C-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 of ortho-hydroxylation (2 and 6 position) with additional conjugation to form the ether sulfates and glucuronides. An N-glucuronide of the parent compound was also identified. 3-Methyl-4-trifluoromethylacetanilide ((13)C-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occurred as ca. 50% of the excreted N-acetylated major metabolites contained no (13)C-label at the acetyl, having been replaced by an endogenous (12)C-acetyl source.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.
authors.affiliation: Biological Chemistry, Division of Biomedical Sciences, Imperial College of Science, Technology and Medicine, Sir Alexander Fleming Building, South Kensington, London, United Kingdom.
authors.forename: G B
authors.initials: GB
authors.lastname: Scarfe
authors.forename: J C
authors.initials: JC
authors.lastname: Lindon
authors.forename: J K
authors.initials: JK
authors.lastname: Nicholson
authors.forename: B
authors.initials: B
authors.lastname: Wright
authors.forename: E
authors.initials: E
authors.lastname: Clayton
authors.forename: I D
authors.initials: ID
authors.lastname: Wilson
mesh_terms: D000813:Anilides / Q000493:pharmacokinetics*; D000814:Aniline Compounds / Q000493:pharmacokinetics*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D006868:Hydrolysis; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C121874:3-methyl-4-trifluoromethylacetanilide; C121873:3-methyl-4-trifluoromethylaniline; D000813:Anilides; D000814:Aniline Compounds