Cancer Chemotherapy and Pharmacology

, Volume 74, Issue 6, pp 1271–1278 | Cite as

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

  • Joel M. Reid
  • Matthew P. Goetz
  • Sarah A. Buhrow
  • Chad Walden
  • Stephanie L. Safgren
  • Mary J. Kuffel
  • Kathryn E. Reinicke
  • Vera Suman
  • Paul Haluska
  • Xiaonan Hou
  • Matthew M. Ames
Original Article
First Online:
Received:
Accepted:

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.

Keywords

Endoxifen Tamoxifen Mouse Pharmacokinetics Estrogen receptor MCF7 

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

Cmax

Maximum plasma concentration

Tmax

Time that the maximum plasma concentration was achieved

Vz

Volume of distribution

Clp

Plasma clearance

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Notes

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.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Joel M. Reid
    • 1
    • 2
  • Matthew P. Goetz
    • 1
  • Sarah A. Buhrow
    • 1
  • Chad Walden
    • 1
  • Stephanie L. Safgren
    • 1
    • 2
  • Mary J. Kuffel
    • 1
  • Kathryn E. Reinicke
    • 1
  • Vera Suman
    • 3
  • Paul Haluska
    • 1
  • Xiaonan Hou
    • 1
  • Matthew M. Ames
    • 1
    • 2
  1. 1.Department of OncologyMayo ClinicRochesterUSA
  2. 2.Department of Molecular Pharmacology and Experimental TherapeuticsMayo ClinicRochesterUSA
  3. 3.Department of BiostatisticsMayo ClinicRochesterUSA

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