Effects of high-dose ketoconazole treatment on adrenal mineralocorticoid biosynthesis in dogs and rats.
At high doses, ketoconazole blocks both testicular and adrenal androgen biosyntheses and partially inhibits the glucocorticoid production. To investigate the effects of this imidazole derivative on the mineralocorticoid biosynthesis, 7 male mongrel dogs received a single oral dose of 15 mg/kg of ketoconazole or placebo, in a cross-over way. From 2 to 4 h after treatment, an iv infusion of angiotensin II (10 ng/kg per min) was performed. Ketoconazole treatment significantly blunted the aldosterone and cortisol increment, whereas 18-hydroxycorticosterone, corticosterone, 11-deoxycorticosterone (DOC), progesterone, and 17 alpha-hydroxyprogesterone rose to peak concentrations, respectively 2.5-, 6-, 8-, 2.5- and 1.5-fold higher than those observed after placebo administration. Plasma 11-deoxycortisol and renin activity levels remained similar in both groups. On the other hand, 2 X 2 groups of 10 male adult rats each were fed with a normal or a sodium-depleted diet. Of the two sets of groups, one was treated ip with ketoconazole (20 mg/kg twice a day), the other with vehicle solution. In animals on either diet, ketoconazole lowered 18-hydroxycorticosterone and aldosterone concentrations. Plasma DOC rose up to 25-fold in the salt-deprived animals. Serum Na+, Cl-, corticosterone and plasma renin activity remained unaffected by the treatment. These results show that high-dose ketoconazole treatment partially inhibits the biosynthesis of aldosterone by affecting the cytochrome P-45011 beta.(ABSTRACT TRUNCATED AT 250 WORDS)
De Coster
R
R
Coene
M C
MC
Haelterman
C
C
Beerens
D
D
Goeminne
N
N
D000450:Aldosterone / Q000096:biosynthesis; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D004039:Diet, Sodium-Restricted; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D007654:Ketoconazole / Q000008:administration & dosage*; D008297:Male; D008901:Mineralocorticoids / Q000096:biosynthesis* / Q000097:blood; D011374:Progesterone / Q000097:blood; D011467:Prostate / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D012083:Renin / Q000097:blood; D013737:Testis / Q000187:drug effects; D013739:Testosterone / Q000097:blood
D008901:Mineralocorticoids; D000804:Angiotensin II; D013739:Testosterone; D000450:Aldosterone; D011374:Progesterone; D012083:Renin; D007654:Ketoconazole