Ketoconazole blocks cortisol secretion in man by inhibition of adrenal 11 beta-hydroxylase.
We investigated basal and ACTH stimulated levels of cortisol, corticosterone, 17 alpha-hydroxyprogesterone, 11-deoxycortisol and 11-deoxycorticosterone as well as plasma levels of ACTH before and during the oral administration of ketoconazole in five patients with Cushing's syndrome (3 with bilateral adrenal hyperplasia, 1 with adrenal adenoma and 1 with adrenal carcinoma) and in three controls. The influence of ketoconazole on the transformation of 3H-17 alpha-hydroxyprogesterone to 3H-11-deoxycortisol and 3H-cortisol and of 3H-11-deoxycortisol to 3H-cortisol as well as of 3H-11-deoxycorticosterone to 3H-corticosterone was also examined in slices or homogenates of normal and hyperplastic adrenal tissue from four patients. Ketoconazole induced a rise of 11-deoxycortisol and 11-deoxycorticosterone, but not of cortisol and inconsistently of corticosterone which were increased by ACTH. Thus the ratio 11-deoxycortisol/cortisol rose more after ketoconazole than after ACTH and the ratio 11-deoxycorticosterone/corticosterone rose after ketoconazole but fell after ACTH. Plasma ACTH levels were stimulated 2-50 fold by ketoconazole. Incubation studies of adrenal tissue slices with 3H-17 alpha-hydroxyprogesterone showed that ketoconazole inhibited the transformation of 3H-17 alpha-hydroxyprogesterone to 3H-cortisol but not to 3H-11-deoxycortisol so that the ratio 3H-11-deoxycortisol/3H-cortisol increased 15-80 fold. After incubation of adrenal slices with 3H-11-deoxycortisol or 3H-11-deoxycorticosterone and ketoconazole, a 2-260 fold increase of the ratios 3H-11-deoxycortisol/3H-cortisol and 3H-11-deoxycorticosterone/3H-corticosterone were also found.
Engelhardt
D
D
Dörr
G
G
Jaspers
C
C
Knorr
D
D
D019326:17-alpha-Hydroxyprogesterone; D000311:Adrenal Glands / Q000201:enzymology; D000324:Adrenocorticotropic Hormone / Q000097:blood; D003345:Corticosterone / Q000097:blood; D003350:Cortodoxone / Q000097:blood; D003480:Cushing Syndrome / Q000188:drug therapy* / Q000201:enzymology; D003900:Desoxycorticosterone / Q000097:blood; D006801:Humans; D006854:Hydrocortisone / Q000097:blood*; D006908:Hydroxyprogesterones / Q000097:blood; D007654:Ketoconazole / Q000627:therapeutic use*; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors*; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors*
D006908:Hydroxyprogesterones; D003900:Desoxycorticosterone; D019326:17-alpha-Hydroxyprogesterone; D000324:Adrenocorticotropic Hormone; D013250:Steroid Hydroxylases; D013252:Steroid 11-beta-Hydroxylase; D007654:Ketoconazole; D003345:Corticosterone; D003350:Cortodoxone; D006854:Hydrocortisone