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 antagonists and inhibitors
  • *Cytochrome P 450 antagonists and inhibitors
  • *Enzyme Inhibitors pharmacology
  • *Microsomes, Liver drug effects
  • *Nitriles pharmacology
  • *Triazoles pharmacology
  • Arimidex
  • Aromatase
  • Comparative Study
  • Cytochrome P 450
  • Cytochrome P 450 CYP1A2
  • Cytochrome P 450 CYP1A2 antagonists and inhibitors
  • Cytochrome P 450 CYP2D6
  • Cytochrome P 450 CYP2D6 antagonists and inhibitors
  • Enzyme Inhibitors
  • Human
  • Hydroxylases
  • Hydroxylases antagonists and inhibitors
  • In Vitro
  • Microsomes, Liver enzymology
  • Nifedipine
  • Nifedipine antagonists and inhibitors
  • Nifedipine metabolism
  • Nitriles
  • Oxidoreductases, N Demethylating
  • Oxidoreductases, N Demethylating antagonists and i
  • Steroid Hydroxylases
  • Steroid Hydroxylases antagonists and inhibitors
  • Substrate Specificity
  • Triazoles
  • coumarin hydroxylase
  • erythromycin N demethylase
  • estradiol 16 alpha hydroxylase

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  • S W Grimm

  • M C Dyroff

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