Abstract
SummaryBackground Lapatinib is a small-molecule tyrosine kinase inhibitor of human epidermal receptor 2 (HER2) and EGFR that has currently been approved for the treatment of HER2-positive advanced and metastatic breast cancer (BC). The ATP-binding cassette (ABC) family of transporters includes P-glycoprotein (P-gp; ABCB1) and breast cancer resistance protein (BCRP; ABCG2), which substantially restrict the penetration of drugs, including chemotherapeutics, through the blood-brain barrier and blood-cerebrospinal fluid barrier. The aim of this study was to investigate the effects of elacridar, an ABCB1 and ABCG2 inhibitor, on the brain and cerebrospinal fluid uptake of lapatinib. Methods Rats were divided into two groups: one group received 5 mg/kg elacridar and 100 mg/kg lapatinib (an experimental group), and the other group received 100 mg/kg lapatinib (a control group). Lapatinib concentrations in the blood plasma (BP), cerebrospinal fluid (CSF) and brain tissue (BT) were measured by liquid chromatography coupled with tandem mass spectrometry. Results Elacridar significantly increased lapatinib penetration into the CSF and BT (Cmax increase of 136.4% and 54.7% and AUC0-∞ increase of 53.7% and 86.5%, respectively). The Cmax of lapatinib in BP was similar in both experimental groups (3057.5 vs. 3257.5 ng/mL, respectively). Conclusion This study showed that elacridar influenced the pharmacokinetics of lapatinib. The inhibition of ABCB1 and ABCG2 transporters by elacridar substantially enhanced the penetration of lapatinib into the CSF and BT. The blocking of protein transporters could become indispensable in the treatment of patients with breast cancer and brain metastases.
Highlights
Breast cancer (BC) is the most common malignant cancer diagnosed in women in Europe and the US
Research has shown that brain accumulation of axitinib, cediranib and crizotinib depends mainly on ABCB1 activity, whereas the brain disposition of sorafenib is predominantly influenced by the ABCG2 protein [23]
Polli et al [31] showed that after 24-h intravenous administration of lapatinib, the Kp,brain tissue (BT) value was only 0.04 in WT mice, but it was 40 times greater in mdr1a/ b(−/−)/bcrp(−/−) mice. These results suggested that both P-gp and breast cancer resistance protein (BCRP) synergistically contributed to the penetration of lapatinib in the brain
Summary
Breast cancer (BC) is the most common malignant cancer diagnosed in women in Europe and the US. BC is the second most common tumor (following lung cancer) with brain metastases (BM). 6–16% of patients with BC have metastases within the central nervous system (CNS) [2, 3]. The treatment of BC patients with BM remains a difficult therapeutic problem. The average survival time of untreated patients is only one month, whereas radiotherapy applied to the CNS extends the survival time to 3–6 months. Even patients with a single CNS lesion who undergo surgery and radiotherapy live only slightly longer, i.e., 10–16 months. The percent of clinically apparent BM is significantly higher (24–48%) in patients with HER2 receptor
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