MOUSE HEPATIC METABOLITES OF KETOCONAZOLE - ISOLATION AND STRUCTURE ELUCIDATION

Oxidation, cleavage and degradation of the imidazole and piperazine ri ngs, O-dealkylation, and aromatic hydroxylation are the reported pathw ays of ketoconazole (KC) metabolism. Metabolites were examined in hepa tic 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 degre es C. A mixture of chloroform/methanol extracts of liver homogenates w ere dried under vacuum and methanol extracts of the residue were chrom atographed by a series of preparative and analytical HPLC techniques. Structure assignments were made by NMR and MS/MS techniques. It was de monstrated that KC was biotransformed to a number of products. Nine we re isolated and seven identified as exclusive products of the biotrans formation 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 H-1-NMR and MS data suggested that the remaining two metabolites were products resul ting from the oxidation of the imidazole ring.