van Hoppe Stéphanie, Sparidans Rolf W, Wagenaar Els, Beijnen Jos H, Schinkel Alfred H
Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Section of Pharmacoepidemiology & Clinical Pharmacology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
Pharmacol Res. 2017 Jun;120:43-50. doi: 10.1016/j.phrs.2017.01.035. Epub 2017 Mar 10.
Afatinib is a highly selective, irreversible inhibitor of EGFR and HER-2. It is orally administered for the treatment of patients with EGFR mutation-positive types of metastatic NSCLC. We investigated whether afatinib is a substrate for the multidrug efflux transporters ABCB1 and ABCG2 and whether these transporters influence oral availability and brain and other tissue accumulation of afatinib. We used in vitro transport assays to assess human (h)ABCB1-, hABCG2- or murine (m)Abcg2-mediated transport of afatinib. To study the single and combined roles of Abcg2 and Abcb1a/1b in oral afatinib disposition, we used appropriate knockout mouse strains. Afatinib was transported well by hABCB1, hABCG2 and mAbcg2 in vitro. Upon oral administration of afatinib, Abcg2, Abcb1a/1b and Abcb1a/1b;Abcg2 mice displayed a 4.2-, 2.4- and 7-fold increased afatinib plasma AUC compared with wild-type mice. Abcg2-deficient strains also displayed decreased afatinib plasma clearance. At 2h, relative brain accumulation of afatinib was not significantly altered in the single knockout strains, but 23.8-fold increased in Abcb1a/1b;Abcg2 mice compared to wild-type mice. Abcg2 and Abcb1a/1b restrict oral availability and brain accumulation of afatinib. Inhibition of these transporters may therefore be of clinical importance for patients with brain (micro)metastases positioned behind an intact blood-brain barrier.
阿法替尼是一种高度选择性、不可逆的表皮生长因子受体（EGFR）和人表皮生长因子受体2（HER-2）抑制剂。它通过口服给药，用于治疗EGFR突变阳性的转移性非小细胞肺癌（NSCLC）患者。我们研究了阿法替尼是否是多药外排转运体ABCB1和ABCG2的底物，以及这些转运体是否会影响阿法替尼的口服可用性以及在脑和其他组织中的蓄积。我们使用体外转运试验来评估人源（h）ABCB1、hABCG2或鼠源（m）Abcg2介导的阿法替尼转运。为了研究Abcg2和Abcb1a/1b在阿法替尼口服处置中的单一及联合作用，我们使用了合适的基因敲除小鼠品系。在体外，阿法替尼能被hABCB1、hABCG2和mAbcg2很好地转运。口服阿法替尼后，与野生型小鼠相比，Abcg2、Abcb1a/1b以及Abcb1a/1b;Abcg2小鼠的阿法替尼血浆曲线下面积（AUC）分别增加了4.2倍、2.4倍和7倍。Abcg2基因缺陷品系的阿法替尼血浆清除率也降低。在2小时时，阿法替尼在单一基因敲除品系中的相对脑蓄积没有显著改变，但与野生型小鼠相比，Abcb1a/1b;Abcg2小鼠中的阿法替尼相对脑蓄积增加了23.8倍。Abcg2和Abcb1a/1b限制了阿法替尼的口服可用性和脑蓄积。因此，对于血脑屏障完整的脑（微）转移患者，抑制这些转运体可能具有临床重要性。
