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• W2022892253 abstract "There have been conflicting observations regarding the effects of ketoconazole on hepatic metabolism. The objectives of these studies were to determine whether ketoconazole was an enzyme inducer or inhibitor in the mouse and then to establish the time frame of these ketoconazole-induced enzyme changes. Ketoconazole was administered (150 mg/kg p.o. × 4 days) to male Swiss Webster mice. Biochemical observations over a period of 6 days following treatment indicated that ketoconazole had a temporal biphasic effect on the liver. Although liver weight and microsomal protein were elevated, all other parameters monitored were lower at 2 h following ketoconazole treatment. At 24 h after the last dose of ketoconazole, hepatic biochemical parameters (liver wt., % liver wt./body wt., microsomal protein, and cytochrome P-450) were statistically elevated, while enzyme activities (benzphetamine N-demethylation, 6β- and 7α-hydroxylation of testosterone, formation of androstenedione and UDP-glucuronyltransferase) were inhibited. At 72 h the ketoconazole-induced changes in the hepatic biochemical parameters were comparable to those observed at 24 h, and enzymatic parameters generally appeared to be induced by ketoconazole, with the exception of benzphetamine N-demethylase and UDP-glucuronyltransferase, which exhibited lower enzyme activities. Ethoxyresorufin O-deethylase, 7α-hydroxylation of testosterone and glutathione S-transferase, on the other hand, were unaltered by ketoconazole treatment. The opposing effects of ketoconazole on benzphetamine N-demethylase and ethylmorphine N-demethylase at 72 h were further examined. Enzyme kinetics studies indicated that ketoconazole did not effect the Michaelis constants (K m ) of the two substrates, but the maximum velocity (V max ) of the reactions was altered. Six days after drug administration all monitored parameters had returned to control values, indicating the hepatic effects of ketoconazole in the male mouse were temporal.Key words: ketoconazole in mice, hepatic effects, biphasic effects, temporal effects, enzymic effect, enzyme inhibition, enzyme induction." @default.
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• W2022892253 date "1990-08-01" @default.
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• W2022892253 title "Hepatic effects of ketoconazole in the male Swiss Webster mouse: temporal changes in drug metabolic parameters" @default.
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• W2022892253 doi "https://doi.org/10.1139/y90-170" @default.
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