INHIBITION OF HUMAN DRUG-METABOLIZING CYTOCHROMES P450 BY ANASTROZOLE, A POTENT AND SELECTIVE INHIBITOR OF AROMATASE

Anastrozole methyl)-1,3-phenylene]bis(2-methylproprionitrile)) is a po tent third-generation inhibitor of aromatase, currently marketed as a treatment for postmenopausal women with advanced breast cancer, While its potency and selectivity for inhibition of estrogen synthesis has b een established in both preclinical and clinical studies, this study u sed in vitro methods to examine the effects of anastrozole on several drug metabolizing CYP enzymes found in human liver, Human liver micros omes were co-incubated with anastrozole and probe substrates far CYP1A 2 (phenacetin), CYP2A6 (coumarin), CYP2C9 (tolbutamide), CYP2D6 (dextr omethorphan), and CYP3A (nifedipine), The formation of the CYP-specifi c metabolites following co-incubation with various anastrozole concent rations was determined to establish IC50 and K-i values for these enzy mes, While anastrozole did not inhibit CYP2A6 and CYP2D6 activities at concentrations below 500 mu M, this compound inhibited CYP1A2, CYP2C9 , and CYP3A activities with K-i values of 8, 10, and 10 mu M, respecti vely, Dixon plots used to determine the K-i values for the inhibition of CYP1A2 and CYP3A activities by anastrozole were biphasic, indicatin g additional lower affinity K-i values, Major metabolites of anastrazo le did not retain the ability to inhibit the metabolism of nifedipine (CYP3A), The results of this study indicate that, although anastrozole can inhibit CYP1A2, 2C9, and 3A-mediated catalytic activities, this c ompound would not be expected to cause clinically significant interact ions with other CYP-metabolized drugs at physiologically relevant conc entrations achieved during therapy with Arimidex (Zeneca, Ltd., Maccle sfield, UK) 1-mg.