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Pharmacokinetics of endoxifen and tamoxifen in female mice: implications for comparative in vivo activity studies

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Abstract

Background

Reduced CYP2D6 metabolism and low Z-endoxifen (ENDX) concentrations may increase the risk of breast cancer recurrence in tamoxifen (TAM)-treated women. Little is known regarding the differences between TAM and ENDX murine pharmacokinetics or the effect of administration route on plasma concentrations of each drug.

Methods

The pharmacokinetics of TAM and ENDX were characterized in female mice.

Results

For subcutaneous [s.c.] and oral TAM (4, 10 and 20 mg/kg), TAM AUC increased in a linear manner, but concentrations of the active metabolites [ENDX and 4-hydroxytamoxifen (4HT)] remained low. For oral TAM (20 mg), 4HT concentrations were tenfold greater (>25 ng/ml) than achievable in TAM-treated humans. Both oral (10–200 mg/kg) and s.c. (2.5–25 mg/kg) ENDX·HCl resulted in a greater than dose-proportional increase in AUC, with eightfold greater ENDX concentrations than an equivalent TAM dose. ENDX accumulated in plasma after 5-day dosing of 25 or 100 mg/kg ENDX·HCl and exceeded target concentrations of 0.1 and 1.0 μM, respectively, by twofold to fourfold.

Conclusions

In murine models, oral ENDX yields substantially higher ENDX concentrations, compared to TAM. The low 4HT and ENDX concentrations observed in mice receiving s.c. TAM mirror the TAM pharmacokinetics in humans with impaired CYP2D6 metabolism. These data support the ongoing development of ENDX as a novel agent for the endocrine treatment of ER-positive breast cancer.

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Abbreviations

CYP2D6:

Cytochrome P450

ENDX:

Endoxifen (4-hydroxy-N-desmethyl tamoxifen)

TAM:

Tamoxifen

4HT:

4-Hydroxytamoxifen

NDMT:

N-Desmethyltamoxifen

ER:

Estrogen receptor

s.c.:

Subcutaneous

i.v.:

Intravenous

HPLC:

High-pressure liquid chromatography

ACN:

Acetonitrile

KH2PO4 :

Monopotassium phosphate

PEG:

Polyethylene glycol

CMC:

Carboxymethylcellulose

CPDA:

Citrate/phosphate/dextrose/adenine anticoagulant solution

AUC:

Area under the plasma concentration–time curve

C max :

Maximum plasma concentration

T max :

Time that the maximum plasma concentration was achieved

Vz:

Volume of distribution

Clp:

Plasma clearance

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Acknowledgments

Supported in part by 1R01CA133049-01 (MPG, MMA), the Mayo Comprehensive Cancer Center Grant (CA15083; MMA, JMR, VS), and the Mayo Clinic Breast Cancer SPORE (CA 116201; MMA, JMR, MPG, PH, XH).

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

    Joel M. Reid, Matthew P. Goetz, Sarah A. Buhrow, Chad Walden, Stephanie L. Safgren, Mary J. Kuffel, Kathryn E. Reinicke, Paul Haluska, Xiaonan Hou & Matthew M. Ames

  2. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

    Joel M. Reid, Stephanie L. Safgren & Matthew M. Ames

  3. Department of Biostatistics, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

    Vera Suman

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  1. Joel M. Reid
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  2. Matthew P. Goetz
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  3. Sarah A. Buhrow
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  4. Chad Walden
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  5. Stephanie L. Safgren
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  7. Kathryn E. Reinicke
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  9. Paul Haluska
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  11. Matthew M. Ames
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Corresponding author

Correspondence to Matthew M. Ames.

Additional information

Joel M. Reid and Matthew P. Goetz have contributed equally to this article.

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Reid, J.M., Goetz, M.P., Buhrow, S.A. et al. Pharmacokinetics of endoxifen and tamoxifen in female mice: implications for comparative in vivo activity studies. Cancer Chemother Pharmacol 74, 1271–1278 (2014). https://doi.org/10.1007/s00280-014-2605-7

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  • DOI: https://doi.org/10.1007/s00280-014-2605-7

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