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.
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Authors | Sagar Agarwal, Ramola Sane, Jose L Gallardo, John R Ohlfest, William F Elmquist |
Journal | The 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 |
PMID | 20421331
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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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
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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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