Inhibition of drug metabolizing cytochrome P450s by the aromatase inhibitor drug letrozole and its major oxidative metabolite 4,4′-methanol- bisbenzonitrile in vitro

Seongwook Jeong, Margaret M. Woo, David A. Flockhart, Zeruesenay Desta

Research output: Contribution to journalArticle

29 Scopus citations


Purpose: To determine the inhibitory potency of letrozole and its main human metabolite, 4,4′-methanol-bisbenzonitrile, on the activities of eight cytochrome P450 (CYP) enzymes. Methods: Letrozole and its metabolite were incubated with human liver microsomes (HLMs) (or expressed CYP isoforms) and NADPH in the absence (control) and presence of the test inhibitor. Results: Letrozole was a potent competitive inhibitor of CYP2A6 (Ki 4.6 ± 0.05 μM and 5.0 ± 2.4 μM in HLMs and CYP2A6, respectively) and a weak inhibitor of CYP2C19 (Ki 42.2 μM in HLMs and 33.3 μM in CYP2C19), while its metabolite showed moderate inhibition of CYP2C19 and CYP2B6. Letrozole or its metabolite had negligible effect on other CYPs. Conclusions: Based on the in vitro Ki values, letrozole is predicted to be a weak inhibitor of CYP2A6 in vivo. Letrozole and its major human metabolite show inhibitory activity towards other CYPs, but clinically relevant drug interactions seem less likely as the Ki values are above the therapeutic plasma concentrations of letrozole.

Original languageEnglish (US)
Pages (from-to)867-875
Number of pages9
JournalCancer Chemotherapy and Pharmacology
Issue number5
StatePublished - Oct 1 2009



  • Aromatase inhibitor
  • Cytochrome P450
  • Drug interaction
  • Letrozole
  • Metabolite

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Toxicology

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