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1. J Pharmacol Exp Ther. 2012 Mar 27. [Epub ahead of print]

Impact of P-glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2) on
the Brain Distribution of a novel B-RAF Inhibitor: Vemurafenib (PLX4032).

Mittapalli RK, Vaidhyanathan S, Sane R, Elmquist WF.

University of Minnesota.

Vemurafenib (PLX4032) is a novel small molecule BRAF inhibitor, recently approved
by US Food and Drug Administration (FDA) for the treatment of patients with
metastatic melanoma with a BRAFV600E mutation. The objective of this study was to
investigate the role of P-glycoprotein (P-gp) and breast cancer resistance
protein (BCRP) on 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
due to active efflux by P-gp and BCRP. Bidirectional flux studies indicated
greater transport in basolateral-to-apical direction than apical-to-basolateral
direction due to active efflux by P-gp and BCRP. Selective P-gp and BCRP
inhibitors zosuquidar and 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, 1.00 ± 0.19 in Mdr1a/b-/-Bcrp1-/- mice, compared to 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 due to 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.

PMID: 22454535 [PubMed - as supplied by publisher]