Response of Plasma Adrenal Steroids to Synthetic ACTH under Ketoconazole in Man

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Abstract
We have investigated the effect of a single oral administration of 600mg ketoconazole, an imidazole derivative used in clinical practice as an antimycotic agent, on the response of plasma adrenocortical steroids to 1-24 ACTH in 5 normal male subjects pretreated with dexamethasone. The 2mg of dexamethasone was administered orally at 2300h on the preceding night, and then a rapid ACTH test was started at 0830h. After a 1 week interval, the ACTH test was repeated in the same manner under the same dexamethasone pretreatment, but 600mg of ketoconazole was given orally at 0500h. The absolute plasma concentration and the increase over the basal level of each steroid after ACTH were evaluated and compared in both conditions with and without ketoconazole administration. A single ingestion of ketoconazolecaused a decrease in both indices of the responsiveness of plasma dehydroepiandrosterone and a rise in the plasma level of 17α-hydroxypregnenolone. The response of plasma aldosterone was clearly blunted by ketoconazole administration, whereas that of plasma corticosterone was clearly increased. Ketoconazole also blocked the response of plasma cortisol with concomitantly increased responses of plasma 11-deoxycortisol and11-deoxycorticosterone. The increased response of plasma corticosterone seemed to be likely due to the severe inhibitory action of ketoconazole on the conversion of corticosterone to aldosterone. These results imply the inhibitory effect of ketoconazole on C17-20-lyase activity and on the conversion of corticosterone to aldosterone, and suggest an inhibitory action on 11β-hydroxylase activity. The effects of ketoconazole on the other enzyme activities in adrenal steroid biosynthesis were also discussed.

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