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.
Whitehouse
L W
LW
Bureau of Drug Research, Banting Research Centre, Health Protection Branch, Ottawa, Canada.
Menzies
A
A
Dawson
B
B
Cyr
T D
TD
By
A W
AW
Black
D B
DB
Zamecnik
J
J
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