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Vol. 27, Issue 8, 880-886, August 1999
College of Pharmacy, Oregon State University, Corvallis, Oregon
Although ketoconazole is extensively metabolized by hepatic
microsomal enzymes, the route of formation and toxicity of suspected metabolites are largely unknown. Reports indicate that
N-deacetyl ketoconazole (DAK) is a major initial
metabolite in mice. DAK may be susceptible to successive oxidative
attacks on the N-1 position by flavin-containing monooxygenases (FMO)
producing potentially toxic metabolites. Previous laboratory findings
have demonstrated that postnatal rat hepatic microsomes metabolize DAK
by NADPH-dependent monooxygenases to two metabolites as determined by
HPLC. Our current investigation evaluated DAK's metabolism in
adult male and female rats and identified metabolites that may be
responsible for ketoconazole's hepatotoxicity. DAK was extensively
metabolized by rat liver microsomal monooxygenases at pH 8.8 in
pyrophosphate buffer containing the glucose 6-phosphate
NADPH-generating system to three metabolites as determined by HPLC. The
initial metabolite of DAK was a secondary hydroxylamine,
N-deacetyl-N-hydroxyketoconazole, which
was confirmed by liquid chromatography/mass spectrometry and NMR
spectroscopy. Extensive metabolism of DAK occurred at pH 8.8 in
pyrophosphate buffer (female 29% and male 53% at 0.25 h; female
55% and male 57% at 0.5 h; and female 62% and male 66% at
1.0 h). Significantly less metabolism of DAK occurred at pH 7.4 in
phosphate buffer (female 11%, male 17% at 0.25 h; female 20%,
male 31% at 0.5 h; and female 27%, male 37% at 1 h). Heat
inactivation of microsomal-FMO abolished the formation of these
metabolites from DAK. SKF-525A did not inhibit this reaction. These
results suggest that DAK appears to be extensively metabolized by adult
FMO-mediated monooxygenation.
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