THE PRECLINICAL PHARMACOLOGY OF ARIMIDEX (ANASTROZOLE - ZD1033) - A POTENT, SELECTIVE AROMATASE INHIBITOR

Anastrozole is a comparatively simple, achiral benzyltriazole derivati ve, ethyl)-1,3-phenylene]bis(2-methylpropiononitrile), that inhibits h uman placental aromatase with an IC50 of 15 nM and elicits maximal act ivity in vivo in rats (inhibition of ovulation and androstenedione-ind uced uterine hypertrophy) and monkeys (lowering of plasma oestradiol) at 0.1 mg/kg p.o. At 30 times this dose, anastrozole does not elevate plasma 11-deoxycorticosterone in monkeys, and at 100 times this dose, does not affect plasma aldosterone levels or Na+/K+ excretion in rats, plasma K+ concentrations in dogs, or cause adrenal hypertrophy in rat s or dogs. It therefore has no discernible effect on adrenocorticoid h ormone synthesis in vivo at very large multiples of its maximally effe ctive aromatase-inhibiting dose. At similar large multiples in rats it displays no oestrogenic, anti-oestrogenic, androgenic, anti-androgeni c, progestogenic, glucocorticoid, antiglucocorticoid or mineralocortic oid activity. Anastrozole is thus a potent and highly selective aromat ase inhibitor, with no intrinsic hormonal activities-a pharmacological profile particularly suitable for the treatment of breast cancer. Cop yright (C) 1996 Elsevier Science Ltd.