The effects of CGS 16949A, an aromatase inhibitor on adrenal mineralocorticoid biosynthesis.

The family of cytochrome P450 enzymes that mediates steroid hydroxylations are distinct but structurally related proteins. Inhibitors of these steroidogenic steps generally exhibit only relative and dose-related specificity. We evaluated an imidazole, cytochrome P450-related inhibitor, CGS 16949A, in postmenopausal patients with metastatic breast cancer. While a relatively specific aromatase inhibitor at daily dosages of 1-2 mg, CGS 16949A significantly blunted cortisol responses to ACTH at a dose of 16 mg daily. To further evaluate other inhibitory effects of this drug, we determined blood levels of aldosterone (ALDO) and 18-hydroxycorticosterone and their respective urinary metabolites, tetrahydroaldosterone and tetrahydro-18-hydroxy-11-dehydrocorticosterone in 16 postmenopausal women receiving CGS 16949A. At a dose of 16 mg/day, CGS 16949A produced significant (P less than 0.001) suppression of both basal and ACTH-stimulated ALDO production. This was accompanied by a significant rise in the blood 18-hydroxycorticosterone/ALDO ratio (11.4 +/- 0.19; normal, less than 2; P less than 0.001), consistent with a corticosterone methyloxidase type II inhibition. A similar significant elevation (7.5 +/- 1.2; normal, less than 5; P less than 0.001) in the urinary tetrahydro-18-hydroxy-11-dehydrocorticosterone/tetrahydroaldosterone ratio was also observed. These results suggest that CGS 16949A is a potent inhibitor of the corticosterone methyloxidase type II enzyme at a dose of 16 mg daily. At doses of 1-2 mg daily, CGS 16949A blocks aromatase without altering basal aldosterone production and, thus, exhibits dose-related specificity.