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Oral Availability and Brain Penetration of the B-RAFV600E Inhibitor Vemurafenib Can Be Enhanced by the P-Glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2) Inhibitor Elacridar

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Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology & Clinical Pharmacology, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands
§ Slotervaart Hospital, Department of Pharmacy & Pharmacology, Louwesweg 6, 1066 EC Amsterdam, The Netherlands
*The Netherlands Cancer Institute, Division of Molecular Oncology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. E-mail: [email protected]. Phone: +31 20 5122046. Fax: +31 20 669 1383.
Cite this: Mol. Pharmaceutics 2012, 9, 11, 3236–3245
Publication Date (Web):September 28, 2012
Copyright © 2012 American Chemical Society

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    Vemurafenib (PLX4032) is a novel tyrosine kinase inhibitor that has clinical efficacy against metastatic melanoma harboring a BRAFV600E mutation. We aimed to establish whether oral availability and brain penetration of vemurafenib could be restricted by the multidrug efflux transporters P-glycoprotein (P-gp/ABCB1) and breast cancer resistance protein (BCRP/ABCG2), as these might limit therapeutic efficacy, especially against brain metastases. In vitro, vemurafenib was efficiently transported by both human ABCB1 and ABCG2, and very efficiently by mouse Abcg2, but not by mouse Abcc2. Upon oral administration of vemurafenib (5 mg/kg), Abcb1a/1b–/– mice had a 1.6-fold increased, Abcg2–/– mice a 2.3-fold increased, and Abcb1a/1b–/–;Abcg2–/– mice a 6.6-fold increased plasma AUC, respectively, compared to wild-type (WT) mice, indicating a marked and additive role of these transporters in limiting vemurafenib oral availability. Brain-to-plasma ratios of vemurafenib (oral, 25 mg/kg) were not increased in Abcg2–/– mice, only 1.7-fold in Abcb1a/1b–/– mice, but 21.4-fold in Abcb1a/1b–/–;Abcg2–/– mice, indicating pronounced overlapping functions of these transporters in reducing vemurafenib brain accumulation. Oral coadministration of the dual ABCB1 and ABCG2 inhibitor elacridar almost completely eliminated the roles of Abcb1 and Abcg2 in restricting oral availability and brain accumulation of vemurafenib. As predicted by previously described pharmacokinetic modeling, halving the amount of active efflux transport at the WT blood–brain barrier by testing heterozygous Abcb1a/1b+/–;Abcg2+/– mice had little impact on vemurafenib brain accumulation. Our data suggest that elacridar coadministration may be considered to improve the therapeutic efficacy of vemurafenib, especially for brain metastases located behind a functional blood–brain barrier.

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    In vitro transepithelial transport of vemurafenib (5 μM) in MDCK-II cells transduced with murine Abcc2 cells and in vivo brain concentrations and relative brain accumulations of female WT and Abcb1a/1b–/–;Abcg2–/– mice after oral administration of 25 mg/kg vemurafenib and 100 mg/kg elacridar. This material is available free of charge via the Internet at

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