Brain accumulation of the EML4-ALK inhibitor ceritinib is restricted by P-glycoprotein (P-GP/ABCB1) and breast cancer resistance protein (BCRP/ABCG2)

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• 作者：Anita Kort^a ; ^c ; Rolf W. Sparidans^b ; Els Wagenaar^a ; Jos H. Beijnen^b ; ^c ; ^d ; Alfred H. Schinkel^a ; ^{a.schinkel@nki.nl" class="auth_mail" title="E-mail the corresponding author}
• 关键词：ABC ; ATP-binding cassette ; ALK ; anaplastic lymphoma kinase ; AUC ; area under the plasma concentration-time curve ; BBB ; blood-brain barrier ; BCRP ; breast cancer resistance protein ; Cmax ; maximum drug concentration in plasma ; EML4 ; echinoderm microtubule-associated protein like-4 ; MDCKII ; Madin&ndash ; Darby canine kidney type II cell line ; NSCLC ; non-small cell lung cancer ; P-gp ; P-glycoprotein ; SD ; standard deviation ; TKI ; tyrosine kinase inhibitor ; Tmax ; time after administration of a drug to reac
• 刊名：Pharmacological Research
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：102
• 期：Complete
• 页码：200-207
• 全文大小：1260 K

文摘

We aimed to clarify the roles of the multidrug transporters ABCB1 and ABCG2 in oral availability and brain accumulation of ceritinib, an oral anaplastic lymphoma kinase (ALK) inhibitor used to treat metastatic non-small cell lung cancer (NSCLC) after progression on crizotinib. Importantly, NSCLC is prone to form brain metastases. Transport of ceritinib by human (h) ABCB1 or hABCG2 or mouse (m) Abcg2 was assessed in vitro. To study the single and combined roles of Abcb1a/1b and Abcg2 in ceritinib disposition in vivo, we used appropriate knockout mouse strains. Ceritinib was very efficiently transported by hABCB1, and efficiently by hABCG2 and mAbcg2 in vitro, and transport was specifically inhibited by the ABCB1 inhibitor zosuquidar and ABCG2 inhibitor Ko143, respectively. Absorption and 24-h oral availability were not significantly affected by the absence of Abcb1 and/or Abcg2, but the brain concentrations were greatly increased (>38-fold) in Abcb1a/1b^−/− mice at 3 and 24 h after oral administration of 20 mg/kg ceritinib. The brain concentrations increased another ∼3-fold (to >90-fold) in Abcb1a/1b;Abcg2^−/− mice, indicating that there was a significant additional effect of Abcg2-mediated transport of ceritinib as well in vivo. Overall, brain accumulation, but not the 24-h oral availability of ceritinib were profoundly restricted by Abcb1a/1b and Abcg2, with Abcb1a/1b being the dominant efflux protein. Our data suggest that coadministration of ceritinib with a dual ABCB1 and ABCG2 inhibitor may improve treatment of brain (micro) metastases positioned behind a functionally intact blood-brain barrier, and possibly also of tumors resistant to ceritinib due to ABCB1 or ABCG2 overexpression.