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Research ArticleMetabolism, Transport, and Pharmacogenomics

Mechanisms Limiting Distribution of the Threonine-Protein Kinase B-RaFV600E Inhibitor Dabrafenib to the Brain: Implications for the Treatment of Melanoma Brain Metastases

Rajendar K. Mittapalli, Shruthi Vaidhyanathan, Arkadiusz Z. Dudek and William F. Elmquist
Journal of Pharmacology and Experimental Therapeutics March 2013, 344 (3) 655-664; DOI: https://doi.org/10.1124/jpet.112.201475
Rajendar K. Mittapalli
Department of Pharmaceutics, Brain-Barriers Research Center (R.K.M., S.V., W.F.E.), and Divison of Hematology, Oncology and Transplantation, Department of Medicine (A.Z.D.), University of Minnesota, Minneapolis, Minnesota
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Shruthi Vaidhyanathan
Department of Pharmaceutics, Brain-Barriers Research Center (R.K.M., S.V., W.F.E.), and Divison of Hematology, Oncology and Transplantation, Department of Medicine (A.Z.D.), University of Minnesota, Minneapolis, Minnesota
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Arkadiusz Z. Dudek
Department of Pharmaceutics, Brain-Barriers Research Center (R.K.M., S.V., W.F.E.), and Divison of Hematology, Oncology and Transplantation, Department of Medicine (A.Z.D.), University of Minnesota, Minneapolis, Minnesota
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William F. Elmquist
Department of Pharmaceutics, Brain-Barriers Research Center (R.K.M., S.V., W.F.E.), and Divison of Hematology, Oncology and Transplantation, Department of Medicine (A.Z.D.), University of Minnesota, Minneapolis, Minnesota
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Abstract

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/b−/−Bcrp1−/− 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.

Footnotes

  • This work was supported in part by the National Institutes of Health National Cancer Institute [Grant CA138437].

  • dx.doi.org/10.1124/jpet.112.201475.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Received October 29, 2012.
  • Accepted December 14, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 344 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 344, Issue 3
1 Mar 2013
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Research ArticleMetabolism, Transport, and Pharmacogenomics

Brain Distribution of Dabrafenib in Mouse

Rajendar K. Mittapalli, Shruthi Vaidhyanathan, Arkadiusz Z. Dudek and William F. Elmquist
Journal of Pharmacology and Experimental Therapeutics March 1, 2013, 344 (3) 655-664; DOI: https://doi.org/10.1124/jpet.112.201475

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Research ArticleMetabolism, Transport, and Pharmacogenomics

Brain Distribution of Dabrafenib in Mouse

Rajendar K. Mittapalli, Shruthi Vaidhyanathan, Arkadiusz Z. Dudek and William F. Elmquist
Journal of Pharmacology and Experimental Therapeutics March 1, 2013, 344 (3) 655-664; DOI: https://doi.org/10.1124/jpet.112.201475
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