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Distribution of gefitinib to the brain is limited by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2)-mediated active efflux.

Abstract
Gefitinib is an orally active inhibitor of the epidermal growth factor receptor approved for use in patients with locally advanced or metastatic non-small cell lung cancer. It has also been evaluated in several clinical trials for treatment of brain tumors such as high-grade glioma. In this study, we investigated the influence of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) on distribution of gefitinib to the central nervous system. In vitro studies conducted in Madin-Darby canine kidney II cells indicate that both P-gp and BCRP effectively transport gefitinib, limiting its intracellular accumulation. In vivo studies demonstrated that transport of gefitinib across the blood-brain barrier (BBB) is significantly limited. Steady-state brain-to-plasma (B/P) concentration ratios were 70-fold higher in the Mdr1a/b(-/-) Bcrp1(-/-) mice (ratio of approximately 7) compared with wild-type mice (ratio of approximately 0.1). The B/P ratio after oral administration increased significantly when gefitinib was coadministered with the dual P-gp and BCRP inhibitor elacridar. We investigated the integrity of tight junctions in the Mdr1a/b(-/-) Bcrp1(-/-) mice and found no difference in the brain inulin and sucrose space between the wild-type and Mdr1a/b(-/-) Bcrp1(-/-) mice. This suggested that the dramatic enhancement in the brain distribution of gefitinib is not due to a leakier BBB in these mice. These results show that brain distribution of gefitinib is restricted due to active efflux by P-gp and BCRP. This finding is of clinical significance for therapy in brain tumors such as glioma, where concurrent administration of a dual inhibitor such as elacridar can increase delivery and thus enhance efficacy of gefitinib.
AuthorsSagar Agarwal, Ramola Sane, Jose L Gallardo, John R Ohlfest, William F Elmquist
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 334 Issue 1 Pg. 147-55 (Jul 2010) ISSN: 1521-0103 [Electronic] United States
PMID20421331 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Abcg2 protein, mouse
  • Acridines
  • Antineoplastic Agents
  • Quinazolines
  • Tetrahydroisoquinolines
  • Elacridar
  • Gefitinib
Topics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors, genetics, physiology)
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters (antagonists & inhibitors, genetics, physiology)
  • Acridines (pharmacology)
  • Animals
  • Antineoplastic Agents (blood, pharmacokinetics)
  • Biological Transport, Active
  • Blood-Brain Barrier (drug effects, metabolism)
  • Brain (drug effects, metabolism)
  • Cell Line
  • Cell Membrane Permeability
  • Dogs
  • Gefitinib
  • Male
  • Mice
  • Mice, Knockout
  • Quinazolines (blood, pharmacokinetics)
  • Tetrahydroisoquinolines (pharmacology)
  • Tissue Distribution
  • Transfection

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