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

Abstract

IntroductionSome 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 methodsIn 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. ResultsThe result showed that RE of gefitinib at the concentrations of 1μM and 10μM 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 200mg/kg. In BM model, AUCtotalbrain/AUCtotalblood in 50mg/kg and 200mg/kg groups were 0.4 and 0.7, respectively, while AUCCSF/AUCfreeblood were 0.21 and 0.18, respectively. Positive correlation between concentration of gefitinib in CSF and pEGFR modulation in the brain tumor was identified. ConclusionGefitinib is a P-gp substrate and has limited active BBB penetration. Increased doses of gefitinib potentially accelerated passive permeability.