Yan Chen1, Mengzhao Wang, Wei Zhong, Jing Zhao. 1. The Respiratory Department of Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Peking 100730, China.
Abstract
INTRODUCTION: Some studies showed that epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib could improve the outcome of non-small-cell lung cancer (NSCLC) patients with brain metastasis (BM), while the concentration of gefitinib in cerebrospinal fluid (CSF) was low. Therefore, we designed the present study to investigate whether gefitinib could actively penetrate blood brain barrier (BBB) in a mouse model of lung cancer brain metastasis (BM). MATERIALS AND METHODS: In vitro MDCK-MDR1 assay was used to determine permeability and efflux ratio (RE) of gefitinib. In vivo pharmacokinetic and pharmacodynamic evaluation was performed in both normal nude mice and a BM model established by intra-carotid artery (ICA) injection of PC-9 cells. RESULTS: The result showed that RE of gefitinib at the concentrations of 1 μM and 10 μM was 4.12 and 4.05, respectively, but significantly decreased to 1 and 1.35 after adding a P-glycoprotein (P-gp) inhibitor, cyclosporine A. In both normal mice and BM model, dose dependent increase of gefitinib was detected in the blood, brain and CSF at the doses of 50, 100 and 200 mg/kg. In BM model, AUC(totalbrain)/AUC(totalblood) in 50 mg/kg and 200 mg/kg groups were 0.4 and 0.7, respectively, while AUC(CSF)/AUC(freeblood) were 0.21 and 0.18, respectively. Positive correlation between concentration of gefitinib in CSF and pEGFR modulation in the brain tumor was identified. CONCLUSION: Gefitinib is a P-gp substrate and has limited active BBB penetration. Increased doses of gefitinib potentially accelerated passive permeability.
INTRODUCTION: Some studies showed that epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib could improve the outcome of non-small-cell lung cancer (NSCLC) patients with brain metastasis (BM), while the concentration of gefitinib in cerebrospinal fluid (CSF) was low. Therefore, we designed the present study to investigate whether gefitinib could actively penetrate blood brain barrier (BBB) in a mouse model of lung cancer brain metastasis (BM). MATERIALS AND METHODS: In vitro MDCK-MDR1 assay was used to determine permeability and efflux ratio (RE) of gefitinib. In vivo pharmacokinetic and pharmacodynamic evaluation was performed in both normal nude mice and a BM model established by intra-carotid artery (ICA) injection of PC-9 cells. RESULTS: The result showed that RE of gefitinib at the concentrations of 1 μM and 10 μM was 4.12 and 4.05, respectively, but significantly decreased to 1 and 1.35 after adding a P-glycoprotein (P-gp) inhibitor, cyclosporine A. In both normal mice and BM model, dose dependent increase of gefitinib was detected in the blood, brain and CSF at the doses of 50, 100 and 200 mg/kg. In BM model, AUC(totalbrain)/AUC(totalblood) in 50 mg/kg and 200 mg/kg groups were 0.4 and 0.7, respectively, while AUC(CSF)/AUC(freeblood) were 0.21 and 0.18, respectively. Positive correlation between concentration of gefitinib in CSF and pEGFR modulation in the brain tumor was identified. CONCLUSION:Gefitinib is a P-gp substrate and has limited active BBB penetration. Increased doses of gefitinib potentially accelerated passive permeability.
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