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P‐glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2) restrict the brain penetration of the Janus family of tyrosine kinase (JAK) inhibitor CYT387

CYT387 is an oral Janus family of tyrosine kinase (JAK) 1/2 inhibitor and currently undergoes Phase I/II clinical trials for myelofibrosis and myeloproliferative neoplasm treatment. We aimed to establish whether the multidrug efflux transporters P‐glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2) restrict oral availability and brain penetration of CYT387. To investigate this, plasma exposure and brain concentrations of CYT387 were analyzed after oral administration of CYT387 to wild type (WT), Abcb1a/1b−/−, Abcg2−/− and Abcb1a/1b−/−;Abcg2−/− mice. Over 8 hours, plasma exposure of CYT387 was similar between all the strains, indicating that these transporters do not limit oral availability of CYT387. Despite the similar systemic exposure, brain concentrations of CYT387 were increased ~10‐fold in the Abcb1a/1b−/−;Abcg2−/− mice, but not in the Abcb1a/1b−/− or Abcg2−/− mice, compared to the WT strain. However, in Abcg2−/− mice brain levels of CYT387 were slightly, albeit not significantly increased, suggesting that CYT387 might be a better substrate of Abcg2 rather than Abcb1a at the blood‐brain barrier. These results overall indicate a marked and additive role of Abcg2−/− and Abcb1a/1b−/− in restricting brain penetration of CYT387.