Studies on the metabolism of 4-fluoroaniline and 4-fluoroacetanilide in rat: formation of 4-acetamidophenol (paracetamol) and its metabolites via defluorination and N-acetylation

1. The urinary metabolic fate of 4-fluoroanirine (4-FA) and 1-[C-13]-4-fluo roacetaniride (4-FAA) has been studied using NMR-based methods after 50 and 100 mg kg(-1) i.p. doses respectively to the male Sprague-Dawley rat. 2. 4-FA was both ortho- and para-hydroxylated. The major metabolite produce d by ortho-hydroxylation was 2-amino-5-fluorophenylsulphate accounting for similar to 30% of the dose. Of the dose, similar to 10% was excreted via pa ra-hydroxylation and the resulting defluorinated metabolites were N-acetyla ted and excreted as sulphate (major), glucuronide (minor) and N-acetyl-cyst einyl (minor) conjugates of 4-acetamidophenol (paracetamol). 3. The major route of metabolism of 1-[C-13]-4-FAA was N-deacetylation and the metabolites excreted in the urine were qualitatively identical to 4-FA. The paracetamol metabolites produced via para-hydroxylation were also a pr oduct of N-deacetylation and reacetylation, as the [C-13]-label was not ret ained. 4. These studies demonstrate the value of [C-13]-labelling in understanding the contribution of N-acetylation, and futile deacetylation-reacetylation reactions, in aniline metabolism. In addition, this work sheds new light on the metabolic lability of certain aromatic fluorine substituents.