Pharmacokinetic and pharmacodynamic study of Gefitinib in a mouse model of non-small-cell lung carcinoma with brain metastasis

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 ( R E ) 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 R E 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 total brain /AUC total blood in 50 mg/kg and 200 mg/kg groups were 0.4 and 0.7, respectively, while AUC CSF /AUC free blood 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.