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-fluoroaniline (4-FA) and 1-[13C]-4-fluoroacetanilide (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 produced by ortho-hydroxylation was 2-amino-5-fluorophenylsulphate accounting for approximately 30% of the dose. Of the dose, approximately 10% was excreted via para-hydroxylation and the resulting defluorinated metabolites were N-acetylated and excreted as sulphate (major), glucuronide (minor) and N-acetyl-cysteinyl (minor) conjugates of 4-acetamidophenol (paracetamol). 3. The major route of metabolism of 1-[13C]-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 product of N-deacetylation and reacetylation, as the [13C]-label was not retained. 4. These studies demonstrate the value of [13C]-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.
Scarfe
G B
GB
Biological Chemistry, Division of Biomedical Sciences, Imperial College School of Medicine, South Kensington, London, UK.
Tugnait
M
M
Wilson
I D
ID
Nicholson
J K
JK
D000082:Acetaminophen / Q000378:metabolism*; D000083:Acetanilides / Q000378:metabolism*; D000107:Acetylation; D000814:Aniline Compounds / Q000378:metabolism*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D005461:Fluorine / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008956:Models, Chemical; D051381:Rats; D017207:Rats, Sprague-Dawley; D016339:Spectrometry, Mass, Fast Atom Bombardment
D000083:Acetanilides; D000814:Aniline Compounds; D005461:Fluorine; C118946:4-fluoroacetanilide; D000082:Acetaminophen; C043455:4-fluoroaniline