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

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Abstract

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 (K i 4.6 ± 0.05 μM and 5.0 ± 2.4 μM in HLMs and CYP2A6, respectively) and a weak inhibitor of CYP2C19 (K i 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 K i 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 K i values are above the therapeutic plasma concentrations of letrozole.

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Abbreviations

CYPs:

Cytochrome P450s

HLMs:

Human liver microsomes

HPLC:

High-performance liquid chromatography

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Acknowledgments

This study was supported in part by a Pharmacogenetics Research Network Grant (U-01 GM61373), which supports the Consortium on Breast Cancer Pharmacogenomics (COBRA), a Clinical Pharmacology training Grant (T32GM008425) and an RO1 grant (1R01GM078501-01A1) from the National Institute of General Medical Sciences, National Institutes of Health (Bethesda, MD), and by a fellowship award to Dr. Jeong from the Research Institute of Medical Science of Chonnam National University, Gwangju, S. Korea.

Conflict of interest statement

The authors have no conflict of interest.

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Author notes

  1. Seongwook Jeong

    Present address: Department of Anesthesiology, Chonnam University Medical School, Gwangju, South Korea

Authors and Affiliations

  1. Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, 1001 West 10th Street, WD Myers Bldg., W7123, Indianapolis, IN, 46202, USA

    Seongwook Jeong, David A. Flockhart & Zeruesenay Desta

  2. Novartis Pharmaceutical Corporation, Florham Park, NJ, USA

    Margaret M. Woo

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  1. Seongwook Jeong
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  2. Margaret M. Woo
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  4. Zeruesenay Desta
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Correspondence to Zeruesenay Desta.

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Jeong, S., Woo, M.M., Flockhart, D.A. et al. Inhibition of drug metabolizing cytochrome P450s by the aromatase inhibitor drug letrozole and its major oxidative metabolite 4,4′-methanol-bisbenzonitrile in vitro. Cancer Chemother Pharmacol 64, 867–875 (2009). https://doi.org/10.1007/s00280-009-0935-7

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  • DOI: https://doi.org/10.1007/s00280-009-0935-7

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