title: Effects of high-dose ketoconazole treatment on adrenal mineralocorticoid biosynthesis in dogs and rats.
abstract: 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)
authors.forename: R
authors.initials: R
authors.lastname: De Coster
authors.forename: M C
authors.initials: MC
authors.lastname: Coene
authors.forename: C
authors.initials: C
authors.lastname: Haelterman
authors.forename: D
authors.initials: D
authors.lastname: Beerens
authors.forename: N
authors.initials: N
authors.lastname: Goeminne
mesh_terms: 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
chemical_list: D008901:Mineralocorticoids; D000804:Angiotensin II; D013739:Testosterone; D000450:Aldosterone; D011374:Progesterone; D012083:Renin; D007654:Ketoconazole