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The impact of P‐glycoprotein and breast cancer resistance protein on the brain pharmacokinetics and pharmacodynamics of a panel of MEK inhibitors
Author(s) -
de Gooijer Mark C.,
Zhang Ping,
Weijer Ruud,
Buil Levi C.M.,
Beijnen Jos H.,
van Tellingen Olaf
Publication year - 2017
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.31052
Subject(s) - pharmacokinetics , pharmacology , medicine , p glycoprotein , abcg2 , selumetinib , mek inhibitor , in vivo , trametinib , pharmacodynamics , context (archaeology) , mapk/erk pathway , atp binding cassette transporter , kinase , transporter , chemistry , biology , drug resistance , multiple drug resistance , paleontology , biochemistry , microbiology and biotechnology , gene
Mitogen/extracellular signal‐regulated kinase (MEK) inhibitors have been tested in clinical trials for treatment of intracranial neoplasms, including glioblastoma (GBM), but efficacy of these drugs has not yet been demonstrated. The blood‐brain barrier (BBB) is a major impediment to adequate delivery of drugs into the brain and may thereby also limit the successful implementation of MEK inhibitors against intracranial malignancies. The BBB is equipped with a range of ATP‐dependent efflux transport proteins, of which P‐gp (ABCB1) and BCRP (ABCG2) are the two most dominant for drug efflux from the brain. We investigated their impact on the pharmacokinetics and target engagement of a panel of clinically applied MEK inhibitors, in order to select the most promising candidate for brain cancers in the context of clinical pharmacokinetics and inhibitor characteristics. To this end, we used in vitro drug transport assays and conducted pharmacokinetic and pharmacodynamic studies in wildtype and ABC‐transporter knockout mice. PD0325901 displayed more promising characteristics than trametinib (GSK1120212), binimetinib (MEK162), selumetinib (AZD6244), and pimasertib (AS703026): PD0325901 was the weakest substrate of P‐gp and BCRP in vitro , its brain penetration was only marginally higher in Abcb1a/b;Abcg2 −/− mice, and efficient target inhibition in the brain could be achieved at clinically relevant plasma levels. Notably, target inhibition could also be demonstrated for selumetinib, but only at plasma levels far above levels in patients receiving the maximum tolerated dose. In summary, our study recommends further development of PD0325901 for the treatment of intracranial neoplasms.