0090-9556/97/2505-0598-0602$02.00/0
DRUG METABOLISM AND DISPOSITION
Copyright © 1997 by The American Society for Pharmacology and Experimental Therapeutics
Vol. 25, No. 5

Inhibition of Human Drug Metabolizing Cytochromes P450 by Anastrozole, a Potent and Selective Inhibitor of Aromatase

Scott W. Grimm and Martin C. Dyroff

Drug Disposition and Metabolism Department, Zeneca Pharmaceuticals

Anastrozole (2,2[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]bis(2-methylproprionitrile)) is a potent 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 been established in both preclinical and clinical studies, this study used in vitro methods to examine the effects of anastrozole on several drug metabolizing CYP enzymes found in human liver. Human liver microsomes were co-incubated with anastrozole and probe substrates for CYP1A2 (phenacetin), CYP2A6 (coumarin), CYP2C9 (tolbutamide), CYP2D6 (dextromethorphan), and CYP3A (nifedipine). The formation of the CYP-specific metabolites following co-incubation with various anastrozole concentrations was determined to establish IC₅₀ and K_i values for these enzymes. While anastrozole did not inhibit CYP2A6 and CYP2D6 activities at concentrations below 500 µM, this compound inhibited CYP1A2, CYP2C9, and CYP3A activities with K_i values of 8, 10, and 10 µM, respectively. Dixon plots used to determine the K_i values for the inhibition of CYP1A2 and CYP3A activities by anastrozole were biphasic, indicating additional lower affinity K_i values. Major metabolites of anastrozole 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 compound would not be expected to cause clinically significant interactions with other CYP-metabolized drugs at physiologically relevant concentrations achieved during therapy with Arimidex (Zeneca, Ltd., Macclesfield, UK) 1-mg.