Mechanisms limiting distribution of the threonine-protein kinase B-RaF V600E inhibitor dabrafenib to the brain: Implications for the treatment of melanoma brain metastases

Rajendar K. Mittapalli, Shruthi Vaidhyanathan, Arkadiusz Z. Dudek, William F. Elmquist

Research output: Contribution to journalArticlepeer-review

107 Scopus citations


Brain metastases are a common cause of death in stage IV metastatic melanoma. Dabrafenib is a BRAF (gene encoding serine/threonine-protein kinase B-Raf) inhibitor that has been developed to selectively target the valine 600 to glutamic acid substitution (BRAFV600E), which is commonly found in metastatic melanoma. Clinical trials with dabrafenib have shown encouraging results;however, the central nervous system distribution of dabrafenib remains unknown. Thus, the objective of the current study was to evaluate the brain distribution of dabrafenib in mice, and to see whether active efflux by P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) restricts its delivery across the blood-brain barrier (BBB). In vitro accumulation studies conducted in Madin-Darby canine kidney II cells indicate that dabrafenib is an avid substrate for both P-gp and BCRP. Directional flux studies revealed greater transport in the basolateral to apical direction with corrected efflux ratios greater than 2 for both P-gp and Bcrp1 transfected cell lines. In vivo, the ratio of area under the concentration-time curve (AUC)brain to AUCplasma (Kp) of dabrafenib after an i.v. dose (2.5 mg/kg) was 0.023, which increased by 18-fold in Mdr1 a/b2/2Bcrp12/2 mice to 0.42. Dabrafenib plasma exposure was ̃2-fold greater in Mdr1 a/b-/-Bcrp1-/- mice as compared with wild-type with an oral dose (25 mg/kg);however, the brain distribution was increased by ̃10-fold with a resulting Kp of 0.25. Further, compared with vemurafenib, another BRAFV600E inhibitor, dabrafenib showed greater brain penetration with a similar dose. In conclusion, the dabrafenib brain distribution is limited in an intact BBB model, and the data presented herein may have clinical implications in the prevention and treatment of melanoma brain metastases.

Original languageEnglish (US)
Pages (from-to)655-664
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
StatePublished - Mar 2013

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