title: Pharmacokinetic and pharmacodynamic study of Gefitinib in a mouse model of non-small-cell lung carcinoma with brain metastasis.
abstract: BACKGROUND
  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).
  
  
  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.
  
  
  CONCLUSIONS
  Gefitinib is a P-gp substrate and has limited active BBB penetration. Increased doses of gefitinib potentially accelerated passive permeability.
authors.affiliation: The Respiratory Department of Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Peking 100730, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Mengzhao
authors.initials: M
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Zhong
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000556:secondary*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology*; D002460:Cell Line; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D011799:Quinazolines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077156:Gefitinib
keywords: Brain metastasis; Cerebrospinal fluid; Gefitinib; Mouse model; Non-small-cell lung carcinoma (NSCLC); Phosphorylated epidermal growth factor receptor (pEGFR)