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 UnknownSubstrateInhibitorDetails Vemurafenib Multidrug resistance-associated protein 1 Protein Humans UnknownSubstrateInhibitorDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareAfatinibVemurafenib The serum concentration of Afatinib can be increased when it is combined with Vemurafenib. AmbrisentanVemurafenib The serum concentration of Ambrisentan can be increased when it is combined with Vemurafenib. ApixabanVemurafenib The serum concentration of Apixaban can be increased when it is combined with Vemurafenib. AvanafilVemurafenib The serum concentration of Avanafil can be increased when it is combined with Vemurafenib. Belantamab mafodotinVemurafenib The serum concentration of Belantamab mafodotin can be increased when it is combined with Vemurafenib.