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.
authors.affiliation: Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Reid
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Goetz
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Buhrow
authors.forename: Chad
authors.initials: C
authors.lastname: Walden
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Safgren
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Kuffel
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Reinicke
authors.forename: Vera
authors.initials: V
authors.lastname: Suman
authors.forename: Paul
authors.initials: P
authors.lastname: Haluska
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Hou
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Ames
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007279:Injections, Subcutaneous; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D013629:Tamoxifen / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen; C016601:afimoxifene; C055492:4-hydroxy-N-desmethyltamoxifen; D019389:Cytochrome P-450 CYP2D6