Mouse hepatic metabolites of ketoconazole: isolation and structure elucidation.
Oxidation, cleavage and degradation of the imidazole and piperazine rings, O-dealkylation, and aromatic hydroxylation are the reported pathways of ketoconazole (KC) metabolism. Metabolites were examined in hepatic extracts from male Swiss Webster mice treated with KC (350 mg kg-1 po x 7 days) in a 0.25% gum tragacanth suspension at 10 ml kg-1. Livers were collected 24 h after the last dose and stored at -70 degrees C. A mixture of chloroform/methanol extracts of liver homogenates were dried under vacuum and methanol extracts of the residue were chromatographed by a series of preparative and analytical HPLC techniques. Structure assignments were made by NMR and MS/MS techniques. It was demonstrated that KC was biotransformed to a number of products. Nine were isolated and seven identified as exclusive products of the biotransformation of the 1-acetylpiperazine moiety of KC. This substituent was biotransformed to the following: piperazine (de-N-acetyl ketoconazole, DAKC), N-carbamylpiperazine, N-formylpiperazine, 2,3-piperazinedione, 2-formamidoethylamine, ethylenediamine and amine. The 1H-NMR and MS data suggested that the remaining two metabolites were products resulting from the oxidation of the imidazole ring.
Bureau of Drug Research, Banting Research Centre, Health Protection Branch, Ottawa, Canada.
L W
LW
Whitehouse
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Menzies
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B
Dawson
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Cyr
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By
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Black
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Zamecnik
D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D007654:Ketoconazole / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D015394:Molecular Structure
D007654:Ketoconazole