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A comparative study of the effects of ketoconazole and fluconazole on 17-beta estradiol production by rat ovaries in vitro.

In this study we have compared the effects of ketoconazole and fluconazole, a novel triazole antifungal agent, on 17-beta estradiol production in rat ovaries in vitro. For both compounds there was a lag phase, immediately after addition to the test system, during which the rate of oestradiol synthesis remained at control values. This may have been due to the time required for uptake of the compound and transfer to its site of action or for depletion of endogenous pools of intermediates. After the lag phase both compounds produced a reduction in the rate of estradiol synthesis. At any given concentration, fluconazole produced a reduction which was substantially less than that observed with ketoconazole. Indeed 2 microM ketoconazole reduced the rate of oestradiol production by greater than 90% while 10 microM fluconazole caused only a 70% reduction. These findings are consistent with reports that these compounds are inhibitors of cytochrome P450 and with the reduced sensitivity of mammalian cytochrome P450 to fluconazole as compared with ketoconazole.