Abstract
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occurred as ca. 50% of the excretedN-acetylated major metabolites contained no13C-label at the acetyl, having been replaced by an endogenous 12C-acetyl source.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.
Footnotes
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Send reprint requests to: Jeremy K. Nicholson, Biological Chemistry, Division of Biomedical Sciences, Imperial College of Science, Technology and Medicine, Sir Alexander Fleming Building, South Kensington, London SW7 2AZ, UK. E-mail: j.nicholson{at}ic.ac.uk
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This work was supported in part by a Studentship (G.B.S.) from The Analytical Division of The Royal Society of Chemistry and Zeneca Pharmaceuticals.
- Abbreviations used are::
- MS
- mass spectrometry
- MeTFMA
- 3-methyl-4-trifluoromethylaniline
- MeTFMAc
- 3-methyl-4-trifluoromethyl-[13C]-acetanilide
- Received March 30, 1999.
- Accepted June 23, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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