Pharmacology of vorozole.
Vorozole (R83842) is a potent and selective, non-steroidal aromatase inhibitor. It is the dextro-enantiomer of the triazole derivative R 76,713. In FSH-stimulated rat granulosa cells, vorozole inhibited aromatase activity with an IC50-value of 1.4 +/- 0.5 nM. In pregnant mare serum gonadotropin (PMSG)-primed female rats, plasma estradiol levels measured 2 h after single oral administration of vorozole were significantly reduced by drug doses of 0.001 mg/kg and higher, with an ED50-value of 0.0034 mg/kg. In ovariectomized nude mice, bearing an estrogen-producing JEG-3 choriocarcinoma, 5 days treatment with vorozole, dose-dependently reduced uterus weight and completely inhibited tumor aromatase, measured ex vivo. Vorozole showed IC50-values higher than 10 microM for inhibition of progesterone synthesis in rat granulosa cells, for inhibition of steroid biosynthesis in isolated rat testicular and adrenal cells and for inhibition of steroid binding to estrogen-, progestin-, androgen- and gluco- and mineralocorticoid-receptors. In LHRH/ACTH-injected male rats and in rats fed a sodium-deprived diet, single oral administration of up to 10 mg/kg vorozole did not affect plasma levels of testicular and adrenal steroids. The compound also had no in vivo estrogen or androgen (ant)agonistic properties. In the DMBA-induced rat mammary carcinoma model, vorozole at an oral dose of 2.5 mg/kg b.i.d. inhibited tumor growth similarly to ovariectomy.
Wouters
W
W
Department of Endocrinology and Oncology, Janssen Research Foundation, Beerse, Belgium.
Van Ginckel
R
R
Krekels
M
M
Bowden
C
C
De Coster
R
R
D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000450:Aldosterone / Q000378:metabolism; D000818:Animals; D047072:Aromatase Inhibitors; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002822:Choriocarcinoma / Q000201:enzymology / Q000473:pathology; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D003345:Corticosterone / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism; D005260:Female; D005640:Follicle Stimulating Hormone / Q000494:pharmacology; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000187:drug effects / Q000378:metabolism*; D011987:Receptors, Steroid / Q000187:drug effects / Q000378:metabolism*; D013737:Testis / Q000187:drug effects / Q000378:metabolism*; D013739:Testosterone / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*; D014594:Uterine Neoplasms / Q000201:enzymology / Q000473:pathology; D014599:Uterus / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism
D047072:Aromatase Inhibitors; D006063:Chorionic Gonadotropin; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone; D011987:Receptors, Steroid; D014230:Triazoles; C060523:vorozole; D013739:Testosterone; D000450:Aldosterone; D004958:Estradiol; D000324:Adrenocorticotropic Hormone; D005640:Follicle Stimulating Hormone; D003345:Corticosterone