Metabolism of Ketoconazole and Deacetylated Ketoconazole by Rat Hepatic Microsomes and Flavin-Containing Monooxygenases
Ketoconazole (KT) has been reported to cause hepatotoxicity, which is probably not mediated through an immunoallergic mechanism. Although KT is extensively metabolized by hepatic microsomal enzymes, the nature, route of formation, and toxicity of suspected metabolites are largely unknown. Recent rep...
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Published in | Drug metabolism and disposition Vol. 25; no. 6; pp. 772 - 777 |
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Main Authors | , |
Format | Journal Article |
Language | English |
Published |
Bethesda, MD
American Society for Pharmacology and Experimental Therapeutics
01.06.1997
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Subjects | |
Online Access | Get full text |
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Summary: | Ketoconazole (KT) has been reported to cause hepatotoxicity, which is probably not mediated through an immunoallergic mechanism.
Although KT is extensively metabolized by hepatic microsomal enzymes, the nature, route of formation, and toxicity of suspected
metabolites are largely unknown. Recent reports indicate that N -deacetyl ketoconazole (DAK) is a major initial metabolite in mice, which, like lipophilic 4-alkylpiperazines, is susceptible
to successive oxidative attacks on the N-1 position producing ring-opened dialdehydes. The rate of formation of DAK from hepatic
rat microsomal incubations of KT was determined by HPLC. The rate of disappearance for KT was almost equal to the rate of
DAK formation: 5.96 and 5.88 μM/hr, respectively. Also, the potential bioactivation of DAK was evaluated by measuring substrate
activity of DAK with purified pig liver flavin-containing monooxygenase (FMO) and rat liver microsomes. Activity was measured
by following DAK-dependent oxygen uptake polarographically at 37°C in pyrophosphate buffer (pH 8.8) containing the glucose-6-phosphate
NADPH-generating system. The K M âs of DAK were 34.6 and 77.4 μM for the purified FMO and rat microsomal FMO, respectively. Lastly, DAK was found to be metabolized
by an NADPH-dependent rat liver microsomal monooxygenases at pH 8.8 to two metabolites as determined by HPLC. Heat inactivation
of rat liver microsomal FMO abolished the formation of these metabolites from DAK. SKF-525A and anti-rat NADPH cytochrome
P450 reductase did not inhibit this reaction. These results suggest that deacetylation of KT yields a major product, DAK,
for further metabolism by microsomal monooxygenases that seem to be FMO-related. |
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ISSN: | 0090-9556 1521-009X |