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Rapid CommunicationShort Communication

Metabolism of Ketoconazole and Deacetylated Ketoconazole by Rat Hepatic Microsomes and Flavin-Containing Monooxygenases

Rosita J. Rodriguez and Daniel Acosta Jr.
Drug Metabolism and Disposition June 1997, 25 (6) 772-777;
Rosita J. Rodriguez
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Daniel Acosta Jr.
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Abstract

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 KM ’s 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.

Footnotes

  • Send reprint requests to: Dr. Daniel Acosta, Jr., College of Pharmacy, Office of the Dean, University of Cincinnati, P.O. Box 670004, Cincinnati, OH 45267-0004.

  • Received October 1, 1996; accepted February 21, 1997.

  • Abbreviations used are::
    KT
    ketoconazole
    CYP
    cytochrome P450
    DAK
    N-deacetyl ketoconazole
    FMO
    flavin-containing monooxygenase
    CL
    clotrimazole
    IgG
    immunoglobulin G
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 25, Issue 6
1 Jun 1997
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Rapid CommunicationShort Communication

Metabolism of Ketoconazole and Deacetylated Ketoconazole by Rat Hepatic Microsomes and Flavin-Containing Monooxygenases

Rosita J. Rodriguez and Daniel Acosta
Drug Metabolism and Disposition June 1, 1997, 25 (6) 772-777;

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Rapid CommunicationShort Communication

Metabolism of Ketoconazole and Deacetylated Ketoconazole by Rat Hepatic Microsomes and Flavin-Containing Monooxygenases

Rosita J. Rodriguez and Daniel Acosta
Drug Metabolism and Disposition June 1, 1997, 25 (6) 772-777;
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