The microsomal metabolism of ketoconazole is revisited using accurate mass LC/MS(n) and deuterium labelling. Structures for sixteen metabolites are proposed from rat and human microsomal metabolism of commercial ketoconazole. Thirteen of the proposed structures are well determined and consistent with all data; five of the proposed structures are less certain. Ten of the metabolites are described for the first time. Reaction phenotyping shows that most of the metabolites arise from CYP3A4, the enzyme known to be well inhibited by ketoconazole.
The effect of graded levels of dietary ascorbic acid on blood and tissue ascorbic acid levels in mice has been studied. Six levels of dietary ascorbic acid (0, 0.076, 0.5, 1, 5 and 8%) were used. Plasma ascorbic acid rose as dietary ascorbic acid intake increased from 1 to 8%. Mice fed a diet with 5 or 8% added ascorbic acid had significantly higher levels of ascorbic acid in the heart, kidney, lung, muscle and spleen than did control mice fed an ascorbic acid-free diet. Mice fed a diet with 1% added ascorbic acid had elevated ascorbic acid levels in the heart, kidney, lung and spleen. No significant change was observed in ascorbic acid level in the brain, adrenal gland or leukocytes in any of the experimental groups. Ascorbic acid level in the eyes was only slightly higher in mice fed a diet containing 8% added ascorbic acid than in control mice. The observation that the kidney had the greatest increase in ascorbic acid content suggests that the kidney may be a very important organ not only in elimination but also in catabolism of this vitamin. A diet containing 0.5 or 0.076% added ascorbic acid did not significantly increase ascorbic acid content in any of the organs studied. Mice fed a diet with 0.076% added ascorbic acid had slightly, but statistically significantly, lower levels of ascorbic acid in the liver, lung, muscle and spleen that control mice. Mice fed a diet with 0.5% added ascorbic acid had a lower ascorbic acid content in the liver and muscle than the controls.(ABSTRACT TRUNCATED AT 250 WORDS)
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