KETOCONAZOLE-INDUCED HEPATIC PHOSPHOLIPIDOSIS IN THE MOUSE AND ITS ASSOCIATION WITH DE-N-ACETYL KETOCONAZOLE

Ketoconazole (KC), an orally effective systemic antifungal agent, has been associated with symptomatic hepatotoxicity with an incidence as l ow as 1 in 2000. Studies from this laboratory have shown that in the m ouse ketoconazole elicit a biphasic effect on drug metabolism and indu ced phospholipidosis, The pathogenesis of the latter, however, has nev er been established. Studies in mice demonstrated that ketoconazole ad ministration induced phospholipid accumulation in the liver in a dose and time dependent fashion; and de-N-acetyl ketoconazole (DAKC), a maj or hepatic metabolite of KC was associated with this biochemical chang e. A comparative biochemical study following equimolar (0.47 nmol/kg p .o. X 7 days) administration of these two compounds indicated that hep atic phospholipids were elevated to a greater extent by DAKC treatment than by KC. Hepatic profiles of KC, DAKC, and other metabolites at 2, 7.5 and 24 h following single and multiple dosing regimens with eithe r KC or DAKC indicated that KC was readily metabolized to DAKC whereas , DAKC appeared to be recalcitrant to metabolism and accumulated in th e liver. In contrast to the biphasic effects of KC on hepatic enzyme a ctivity observed previously following the administration of KC (enzyme inhibition as well as induction), the biological effects of DAKC were consistent with only an enzyme inhibitory effect: liver microsomal pr otein was not elevated; cytochrome P-450 was depressed; and ethylmorph ine N-demethylase and benzphetamine N-demethylase were inhibited, Cons equently the induction of phospholipidosis and the inhibition of drug metabolism associated with ketoconazole treatment were attributed to D AKC, whereas the inductive properties of KC were ascribed to the uncha nged drug. The dramatic difference in the biological effects of these two compounds was attributed to differences in the orientation of thes e agents in lipid membranes. These results offer an explanation for th e previously observed apparent inhibitory effects of KC on enzyme acti vities (Whitehouse et al. (1990b) Hepatic effects of ketoconazole in t he male Swiss Webster mouse: temporal changes in drug metabolic parame ters. Can. J. Physiol. Pharmacol., 68, 1136-1142) and suggest that DAK C may be the chemical entity responsible for the induction of phosphol ipidosis following ketoconazole administration.