Effect of ketoconazole on the 11-hydroxylation step of adrenal steroidogenesis.
We studied the effect of ketoconazole on glucocorticoid metabolism in three patients before and after a continuous four-hour infusion of ACTH. A single 400 mg oral dose of ketoconazole caused a decrease in serum cortisol concentration, while the concentration of 11-deoxycortisol and its ratio to cortisol increased. The decrease in serum cortisol levels was not accompanied by an increase in plasma ACTH concentration. A four-hour continuous infusion of ACTH resulted in an appropriate elevation of serum cortisol, but with a marked increase in serum concentration of 11-deoxycortisol and its ratio to serum cortisol. We conclude that 400 mg of ketoconazole can decrease cortisol synthesis apparently through a partial block of the 11-beta-hydroxylation step; the observed degree of inhibition may not be sufficient to stimulate the hypothalamic-pituitary-adrenal axis or to cause overt symptoms or signs of adrenal insufficiency; and this partial block of the 11-beta-hydroxylation step becomes more evident during a continuous infusion of ACTH, which can stimulate a normal response of cortisol.
D000284:Administration, Oral; D000311:Adrenal Glands / Q000187:drug effects* / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000008:administration & dosage / Q000494:pharmacology; D000368:Aged; D003350:Cortodoxone / Q000097:blood; D004347:Drug Interactions; D005938:Glucocorticoids / Q000378:metabolism*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007262:Infusions, Intravenous; D007654:Ketoconazole / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D013997:Time Factors
D005938:Glucocorticoids; D000324:Adrenocorticotropic Hormone; D007654:Ketoconazole; D003350:Cortodoxone; D006854:Hydrocortisone