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Research ArticleArticle

Factors Influencing the CNS Distribution of a Novel MEK-1/2 Inhibitor: Implications for Combination Therapy for Melanoma Brain Metastases

Shruthi Vaidhyanathan, Rajendar K. Mittapalli, Jann N. Sarkaria and William F. Elmquist
Drug Metabolism and Disposition August 2014, 42 (8) 1292-1300; DOI: https://doi.org/10.1124/dmd.114.058339
Shruthi Vaidhyanathan
Department of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota (S.V., R.K.M., W.F.E.); and Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (J.N.S.)
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Rajendar K. Mittapalli
Department of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota (S.V., R.K.M., W.F.E.); and Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (J.N.S.)
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Jann N. Sarkaria
Department of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota (S.V., R.K.M., W.F.E.); and Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (J.N.S.)
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William F. Elmquist
Department of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota (S.V., R.K.M., W.F.E.); and Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (J.N.S.)
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Abstract

Brain metastases are a major cause of mortality in patients with advanced melanoma. Adequate brain distribution of targeted agents for melanoma will be critical for treatment success. Recently, improvement in overall survival led to US Food and Drug Administration (FDA) approval of the v-raf murine sarcoma viral oncogene homolog B (BRAF) inhibitors, vemurafenib and dabrafenib, and the mitogen-activated protein kinase kinase-1 (MEK)-1/2 inhibitor, trametinib. However, brain metastases and emergence of resistance remain a significant problem. MEK-1/2 is downstream of BRAF in the mitogen-activated protein kinase (MAPK) signaling pathway, making it an attractive target to combat resistance. The recently approved combination of dabrafenib and trametinib has shown improvement in progression-free survival; however, adequate brain distribution of both compounds is required to effectively treat brain metastases. In previous studies, we found limited brain distribution of dabrafenib. The purpose of the current study was to investigate factors influencing the brain distribution of trametinib. In vitro studies indicated that trametinib is a substrate for both P-glycoprotein (P-gp) and Bcrp, efflux transporters found at the blood-brain barrier. In vivo studies in transgenic mouse models confirmed that P-gp plays an important role in restricting brain distribution of trametinib. The brain-to-plasma partition coefficient (AUCbrain/AUCplasma) was approximately 5-fold higher in Mdr1a/b(−/−) (P-gp knockout) and Mdr1a/b(−/−)Bcrp1(−/−) (triple knockout) mice when compared with wild-type and Bcrp1(−/−) (Bcrp knockout) mice. The brain distribution of trametinib was similar between the wild-type and Bcrp knockout mice. These results show that P-gp plays an important role in limiting brain distribution of trametinib and may have important implications for use of trametinib as single agent or in combination therapy for treatment of melanoma brain metastases.

Footnotes

    • Received March 28, 2014.
    • Accepted May 27, 2014.
  • This work was supported in part by the National Institutes of Health National Cancer Institute [Grants CA138437 (to W.F.E.) and NS077921 (to W.F.E and J.N.S.)]. Financial support for S.V. was provided in part by the Ronald J. Sawchuk Fellowship in Pharmacokinetics of the Department of Pharmaceutics, University of Minnesota.

  • dx.doi.org/10.1124/dmd.114.058339.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (8)
Drug Metabolism and Disposition
Vol. 42, Issue 8
1 Aug 2014
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Research ArticleArticle

Trametinib Distribution to the Brain

Shruthi Vaidhyanathan, Rajendar K. Mittapalli, Jann N. Sarkaria and William F. Elmquist
Drug Metabolism and Disposition August 1, 2014, 42 (8) 1292-1300; DOI: https://doi.org/10.1124/dmd.114.058339

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Research ArticleArticle

Trametinib Distribution to the Brain

Shruthi Vaidhyanathan, Rajendar K. Mittapalli, Jann N. Sarkaria and William F. Elmquist
Drug Metabolism and Disposition August 1, 2014, 42 (8) 1292-1300; DOI: https://doi.org/10.1124/dmd.114.058339
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