Drug metabolism and disposition : the biological fate of chemicals
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Drug Metab. Dispos. · Aug 2014
Factors influencing the CNS distribution of a novel MEK-1/2 inhibitor: implications for combination therapy for melanoma brain metastases.
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. ⋯ 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.