Aromatase inhibition by R 76713: experimental and clinical pharmacology.
R 76713 is a new non-steroidal compound which inhibits aromatase in vitro and in vivo with a potency of at least 1000-fold that of aminoglutethimide. In male cynomolgus monkeys peripheral conversion of labeled androstenedione to estrone is decreased by 85%, 4-5 h after a single intravenous dose of 0.003 mg/kg of R 76713, without altering steroid metabolic clearance rates. In rats fed a sodium-depleted diet for 3 weeks, plasma levels of aldosterone and plasma renin activity remain unchanged 2 h after a single oral dose of up to 20 mg/kg of R 76713. This confirms previous data on the selectivity of R 76713 for aromatase inhibition as compared to inhibition of other enzymes involved in steroid biosynthesis. In male volunteers, a single oral dose of 5 or 10 mg of R 76713 lowers median plasma estradiol levels from 70 pM to the detection limit of the assay (30 pM) 4 and 8 h after intake, whereas no important changes are detected after placebo administration. In 15 premenopausal female volunteers receiving a single oral dose of 20 mg of R 76713, mean plasma estradiol levels decrease from 415 pM (before) to 179, 149 and 185 pM respectively 4, 8 and 24 h after intake whereas they remain above 380 pM after placebo (n = 7).
Wouters
W
W
Department of Endocrinology and Oncology, Janssen Research Foundation, Beerse, Belgium.
De Coster
R
R
Tuman
R W
RW
Bowden
C R
CR
Bruynseels
J
J
Vanderpas
H
H
Van Rooy
P
P
Amery
W K
WK
Janssen
P A
PA
D000328:Adult; D000450:Aldosterone / Q000096:biosynthesis / Q000097:blood*; D000818:Animals; D047072:Aromatase Inhibitors; D004039:Diet, Sodium-Restricted; D004958:Estradiol / Q000097:blood*; D005260:Female; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D012083:Renin / Q000097:blood; D014230:Triazoles / Q000494:pharmacology*
D047072:Aromatase Inhibitors; D014230:Triazoles; C060523:vorozole; D000450:Aldosterone; D004958:Estradiol; D012083:Renin