title: 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.
abstract: 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.
authors.affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Selvi
authors.initials: S
authors.lastname: Durmus
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Sparidans
authors.forename: Els
authors.initials: E
authors.lastname: Wagenaar
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Schinkel
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000502:physiology; D000166:Acridines / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000187:drug effects*; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D018345:Mice, Knockout; D000089762:Multidrug Resistance-Associated Protein 2; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*; D014018:Tissue Distribution; D000077484:Vemurafenib
chemical_list: C000715087:ABCC2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D000166:Acridines; D004338:Drug Combinations; D007211:Indoles; D000089762:Multidrug Resistance-Associated Protein 2; D013449:Sulfonamides; D044005:Tetrahydroisoquinolines; D000077484:Vemurafenib; C083501:Elacridar