Vemurafenib (
PLX4032) is a novel
tyrosine kinase inhibitor that has clinical efficacy against metastatic
melanoma harboring a BRAF(V600E) 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.