PHARMACOLOGY OF VOROZOLE

Vorozole (R83842) is a potent and selective, non-steroidal aromatase i nhibitor. It is the dextro-enantiomer of the triazole derivative R 76 713. In FSH-stimulated rat granulosa cells, vorozole inhibited aromata se activity with an IC50-value of 1.4 +/- 0.5 nM. In pregnant mare ser um gonadotropin (PMSG)-primed female rats, plasma estradiol levels mea sured 2 h after single oral administration of vorozole were significan tly reduced by drug doses of 0.001 mg/kg and higher, with an ED50-valu e of 0.0034 mg/kg. In ovariectomized nude mice, bearing an estrogen-pr oducing JEG-3 choriocarcinoma, 5 days treatment with vorozole, dose-de pendently reduced uterus weight and completely inhibited tumor aromata se, measured ex vivo. Vorozole showed IC50-values higher than 10 muM f or inhibition of progesterone synthesis in rat granulosa cells, for in hibition of steroid biosynthesis in isolated rat testicular and adrena l cells and for inhibition of steroid binding to estrogen-, progestin- , androgen- and gluco- and mineralocorticoid-receptors. In LHRH/ACTH-i njected 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 ra t mammary carcinoma model, vorozole at an oral dose of 2.5 mg/kg b.i.d . inhibited tumor growth similarly to ovariectomy.