Impact of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) on the brain distribution of a novel BRAF inhibitor: vemurafenib (PLX4032).

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Mittapalli RK, Vaidhyanathan S, Sane R, Elmquist WF

Impact of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) on the brain distribution of a novel BRAF inhibitor: vemurafenib (PLX4032).

J Pharmacol Exp Ther. 2012 Jul;342(1):33-40. doi: 10.1124/jpet.112.192195. Epub 2012 Mar 27.

PubMed ID

22454535 [ View in PubMed

]

Abstract

Vemurafenib [N-(3-{[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl}-2,4-difluoroph enyl)propane-1-sulfonamide(PLX4032)] is a novel small-molecule BRAF inhibitor, recently approved by the Food and Drug Administration for the treatment of patients with metastatic melanoma with a BRAF(V600E) mutation. The objective of this study was to investigate the role of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in the distribution of vemurafenib to the central nervous system. In vitro studies conducted in transfected Madin-Darby canine kidney II cells show that the intracellular accumulation of vemurafenib is significantly restricted because of active efflux by P-gp and BCRP. Bidirectional flux studies indicated greater transport in the basolateral-to-apical direction than the apical-to-basolateral direction because of active efflux by P-gp and BCRP. The selective P-gp and BCRP inhibitors zosuquidar and (3S,6S,12aS)-1,2,3,4,6,7,12,12a-octahydro-9-methoxy-6-(2-methylpropyl)-1,4-dioxop yrazino(1',2':1,6)pyrido(3,4-b)indole-3-propanoic acid-1,1-dimethylethyl ester (Ko143) were able to restore the intracellular accumulation and bidirectional net flux of vemurafenib. The in vivo studies revealed that the brain distribution coefficient (area under the concentration time profile of brain/area under the concentration time profile of plasma) of vemurafenib was 0.004 in wild-type mice. The steady-state brain-to-plasma ratio of vemurafenib was 0.035 +/- 0.009 in Mdr1a/b(-/-) mice, 0.009 +/- 0.006 in Bcrp1(-/-) mice, and 1.00 +/- 0.19 in Mdr1a/b(-/-)Bcrp1(-/-) mice compared with 0.012 +/- 0.004 in wild-type mice. These data indicate that the brain distribution of vemurafenib is severely restricted at the blood-brain barrier because of active efflux by both P-gp and BCRP. This finding has important clinical significance given the ongoing trials examining the efficacy of vemurafenib in brain metastases of melanoma.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Vemurafenib	ATP-binding cassette sub-family G member 2	Protein	Humans	Unknown	Substrate Inhibitor	Details
Vemurafenib	Multidrug resistance-associated protein 1	Protein	Humans	Unknown	Substrate Inhibitor	Details

Drug Interactions

Drugs	Interaction
Integrate drug-drug interactions in your software
Afatinib Vemurafenib	The serum concentration of Afatinib can be increased when it is combined with Vemurafenib.
Ambrisentan Vemurafenib	The serum concentration of Ambrisentan can be increased when it is combined with Vemurafenib.
Apixaban Vemurafenib	The serum concentration of Apixaban can be increased when it is combined with Vemurafenib.
Avanafil Vemurafenib	The serum concentration of Avanafil can be increased when it is combined with Vemurafenib.
Belantamab mafodotin Vemurafenib	The serum concentration of Belantamab mafodotin can be increased when it is combined with Vemurafenib.