Lapatinib distribution in HER2 overexpressing experimental brain metastases of breast cancer

Pharm Res. 2012 Mar;29(3):770-81. doi: 10.1007/s11095-011-0601-8. Epub 2011 Oct 20.


Purpose: Lapatinib, a small molecule EGFR/HER2 inhibitor, partially inhibits the outgrowth of HER2+ brain metastases in preclinical models and in a subset of CNS lesions in clinical trials of HER2+ breast cancer. We investigated the ability of lapatinib to reach therapeutic concentrations in the CNS following (14)C-lapatinib administration (100 mg/kg p.o. or 10 mg/kg, i.v.) to mice with MDA-MD-231-BR-HER2 brain metastases of breast cancer.

Methods: Drug concentrations were determined at differing times after administration by quantitative autoradiography and chromatography.

Results: (14)C-Lapatinib concentration varied among brain metastases and correlated with altered blood-tumor barrier permeability. On average, brain metastasis concentration was 7-9-fold greater than surrounding brain tissue at 2 and 12 h after oral administration. However, average lapatinib concentration in brain metastases was still only 10-20% of those in peripheral metastases. Only in a subset of brain lesions (17%) did lapatinib concentration approach that of systemic metastases. No evidence was found of lapatinib resistance in tumor cells cultured ex vivo from treated brains.

Conclusions: Results show that lapatinib distribution to brain metastases of breast cancer is partially restricted and blood-tumor barrier permeability is a key component of lapatinib therapeutic efficacy which varies between tumors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacokinetics*
  • Antineoplastic Agents / pharmacology
  • Brain / drug effects
  • Brain / metabolism
  • Brain / pathology*
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / genetics
  • Brain Neoplasms / pathology
  • Brain Neoplasms / secondary*
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Female
  • Injections, Intravenous
  • Lapatinib
  • Mice
  • Quinazolines / administration & dosage
  • Quinazolines / pharmacokinetics*
  • Quinazolines / pharmacology
  • Receptor, ErbB-2 / antagonists & inhibitors
  • Receptor, ErbB-2 / genetics*
  • Up-Regulation


  • Antineoplastic Agents
  • Quinazolines
  • Lapatinib
  • Receptor, ErbB-2