PT  - JOURNAL ARTICLE
AU  - Sagar Agarwal
AU  - Ramola Sane
AU  - Jose L. Gallardo
AU  - John R. Ohlfest
AU  - William F. Elmquist
TI  - Distribution of Gefitinib to the Brain Is Limited by P-glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2)-Mediated Active Efflux
AID  - 10.1124/jpet.110.167601
DP  - 2010 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 147--155
VI  - 334
IP  - 1
4099  - http://jpet.aspetjournals.org/content/334/1/147.short
4100  - http://jpet.aspetjournals.org/content/334/1/147.full
SO  - J Pharmacol Exp Ther2010 Jul 01; 334
AB  - 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. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics