Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, 1406 Coulter Drive, Amarillo, Texas 79106, USA.
Pharm Res. 2012 Mar;29(3):770-81. doi: 10.1007/s11095-011-0601-8. Epub 2011 Oct 20.
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.
Drug concentrations were determined at differing times after administration by quantitative autoradiography and chromatography.
(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.
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.
拉帕替尼是一种小分子 EGFR/HER2 抑制剂，在临床前模型和 HER2+乳腺癌临床试验中，它能部分抑制 HER2+脑转移瘤的生长和部分中枢神经系统（CNS）病变。我们研究了拉帕替尼在口服（100mg/kg 或 10mg/kg）或静脉注射（10mg/kg）给药后，能否在携带 MDA-MD-231-BR-HER2 脑转移的乳腺癌小鼠中达到 CNS 治疗浓度。
通过定量放射自显影和色谱法，在不同时间测定给药后药物浓度。
（14）C-拉帕替尼浓度在脑转移瘤之间存在差异，与血脑屏障通透性改变有关。平均而言，口服给药后 2 和 12 小时，脑转移瘤浓度是周围脑组织的 7-9 倍。然而，脑转移瘤中的拉帕替尼浓度平均仍仅为外周转移瘤的 10-20%。只有在一小部分脑病变（17%）中，拉帕替尼浓度接近全身转移瘤。在从治疗后的大脑中培养的肿瘤细胞中，没有发现拉帕替尼耐药的证据。
结果表明，拉帕替尼向乳腺癌脑转移瘤的分布部分受限，血脑屏障通透性是拉帕替尼疗效的关键组成部分，其在不同肿瘤之间存在差异。
