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

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

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1271-1278
Number of pages8
JournalCancer Chemotherapy and Pharmacology
Volume74
Issue number6
DOIs
StatePublished - Oct 9 2014

Fingerprint

Pharmacokinetics
Tamoxifen
Cytochrome P-450 CYP2D6
Metabolism
Area Under Curve
4-hydroxy-N-desmethyltamoxifen
Breast Neoplasms
Plasmas
Metabolites
Mirrors

Keywords

  • Endoxifen
  • Estrogen receptor
  • MCF7
  • Mouse
  • Pharmacokinetics
  • Tamoxifen

ASJC Scopus subject areas

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

Cite this

Pharmacokinetics of endoxifen and tamoxifen in female mice : Implications for comparative in vivo activity studies. / Reid, Joel M; Goetz, Matthew Philip; Buhrow, Sarah A.; Walden, Chad; Safgren, Stephanie L.; Kuffel, Mary J.; Reinicke, Kathryn E.; Suman, Vera Jean; Haluska, Paul; Hou, Xiaonan; Ames, Matthew M.

In: Cancer Chemotherapy and Pharmacology, Vol. 74, No. 6, 09.10.2014, p. 1271-1278.

Research output: Contribution to journalArticle

Reid, Joel M ; Goetz, Matthew Philip ; Buhrow, Sarah A. ; Walden, Chad ; Safgren, Stephanie L. ; Kuffel, Mary J. ; Reinicke, Kathryn E. ; Suman, Vera Jean ; Haluska, Paul ; Hou, Xiaonan ; Ames, Matthew M. / Pharmacokinetics of endoxifen and tamoxifen in female mice : Implications for comparative in vivo activity studies. In: Cancer Chemotherapy and Pharmacology. 2014 ; Vol. 74, No. 6. pp. 1271-1278.
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title = "Pharmacokinetics of endoxifen and tamoxifen in female mice: Implications for comparative in vivo activity studies",
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, Estrogen receptor, MCF7, Mouse, Pharmacokinetics, Tamoxifen",
author = "Reid, {Joel M} and Goetz, {Matthew Philip} and Buhrow, {Sarah A.} and Chad Walden and Safgren, {Stephanie L.} and Kuffel, {Mary J.} and Reinicke, {Kathryn E.} and Suman, {Vera Jean} and Paul Haluska and Xiaonan Hou and Ames, {Matthew M.}",
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TY - JOUR

T1 - Pharmacokinetics of endoxifen and tamoxifen in female mice

T2 - Implications for comparative in vivo activity studies

AU - Reid, Joel M

AU - Goetz, Matthew Philip

AU - Buhrow, Sarah A.

AU - Walden, Chad

AU - Safgren, Stephanie L.

AU - Kuffel, Mary J.

AU - Reinicke, Kathryn E.

AU - Suman, Vera Jean

AU - Haluska, Paul

AU - Hou, Xiaonan

AU - Ames, Matthew M.

PY - 2014/10/9

Y1 - 2014/10/9

N2 - 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.

AB - 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.

KW - Endoxifen

KW - Estrogen receptor

KW - MCF7

KW - Mouse

KW - Pharmacokinetics

KW - Tamoxifen

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U2 - 10.1007/s00280-014-2605-7

DO - 10.1007/s00280-014-2605-7

M3 - Article

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AN - SCOPUS:84922079643

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