Given the prevalence of BRAFV600E mutations in a large number of melanomas, BRAF has been an attractive treatment target for patients with melanoma who have the V600E mutation. Vemurafenib (PLX4032) is a small-molecule inhibitor of mutated BRAF. A major factor contributing to the rapid and near 100% mortality in patients with melanoma with brain metastases has been the presumed limited ability of chemotherapeutics to cross the blood-brain barrier. The study by Mittapalli et al. investigated the role of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) on the distribution of vemurafenib to the central nervous system. Intracellular accumulation of vemurafenib was significantly restricted due to active efflux by P-gp and BCRP. 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-dioxopyrazino(1′,2′:1,6)pyrido(3,4-b) indole-3-propanoic acid 1,1-dimethylethyl ester (Ko143) were able to restore the intracellular accumulation of vemurafenib in vitro. Brain exposure of vemurafenib was significantly increased by the genetic knockout of both Mdr1 (P-gp) and BCRP. Using in vitro models, vemurafenib is an avid substrate for both P-gp and BCRP, and in vivo studies using genetic knockout mice indicate both transporters play a significant role in limiting the central nervous system distribution of vemurafenib. This finding has important clinical significance given the ongoing trials examining the efficacy of vemurafenib in brain metastases of melanoma.
See article at J Pharmacol Exp Ther 2012, 342:33–40.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics