Mouse hepatic metabolites of ketoconazole: Isolation and structure elucidation
| Autor: | Brian A. Dawson, Larry W. Whitehouse, J. Zamecnik, A. Menzies, D.B. Black, Terry D. Cyr, A.W. By |
|---|---|
| Rok vydání: | 1994 |
| Předmět: |
Male
Magnetic Resonance Spectroscopy Metabolite Clinical Biochemistry Pharmaceutical Science High-performance liquid chromatography Mass Spectrometry Analytical Chemistry Mice chemistry.chemical_compound Biotransformation Drug Discovery medicine Animals Imidazole Chromatography High Pressure Liquid Spectroscopy Chromatography Chloroform Molecular Structure Chemistry Piperazine Ketoconazole Liver Drug metabolism medicine.drug |
| Zdroj: | Journal of Pharmaceutical and Biomedical Analysis. 12:1425-1441 |
| ISSN: | 0731-7085 |
| Popis: | 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 × 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°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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|