Inhibition of human drug metabolizing cytochromes P450 by anastrozole, a potent and selective inhibitor of aromatase.

  • Grimm S
  • Dyroff M
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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 Ki values for these enzymes. While anastrozole did not inhibit CYP2A6 and CYP2D6 activities at concentrations below 500 microM, this compound inhibited CYP1A2, CYP2C9, and CYP3A activities with Ki values of 8, 10, and 10 microM, respectively. Dixon plots used to determine the Ki values for the inhibition of CYP1A2 and CYP3A activities by anastrozole were biphasic, indicating additional lower affinity Ki 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.

Author-supplied keywords

  • Aromatase Inhibitors
  • Aryl Hydrocarbon Hydroxylases
  • Cytochrome P-450 CYP1A2
  • Cytochrome P-450 CYP1A2 Inhibitors
  • Cytochrome P-450 CYP2A6
  • Cytochrome P-450 CYP2C9
  • Cytochrome P-450 CYP2D6 Inhibitors
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Humans
  • In Vitro Techniques
  • Microsomes, Liver
  • Mixed Function Oxygenases
  • Nifedipine
  • Nitriles
  • Oxidoreductases, N-Demethylating
  • Steroid 16-alpha-Hydroxylase
  • Steroid Hydroxylases
  • Substrate Specificity
  • Triazoles
  • antagonists & inhibitors
  • drug effects
  • enzymology
  • metabolism
  • pharmacology

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  • S W Grimm

  • M C Dyroff

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