Ponatinib is an oral BCR-ABL1 inhibitor for treatment of advanced leukemic diseases that carry the Philadelphia chromosome, specifically containing the T315I mutation yielding resistance to previously approved BCR-ABL1 inhibitors. Using in vitro transport assays and knockout mouse models, we investigated whether the multidrug efflux transporters ABCB1 and ABCG2 transport ponatinib and whether they, or the drug-metabolizing enzyme CYP3A, affect the oral availability and brain accumulation of ponatinib and its active N-desmethyl metabolite (DMP). In vitro, mouse Abcg2 and human ABCB1 modestly transported ponatinib. In mice, both Abcb1 and Abcg2 markedly restricted brain accumulation of ponatinib and DMP, but not ponatinib oral availability. Abcg2 deficiency increased DMP plasma levels ∼3-fold. Cyp3a deficiency increased the ponatinib plasma AUC 1.4-fold. Our results suggest that pharmacological inhibition of ABCG2 and ABCB1 during ponatinib therapy might benefit patients with brain (micro)metastases positioned behind an intact blood-brain barrier, or with substantial expression of these transporters in the malignant cells. CYP3A inhibitors might increase ponatinib oral availability, enhancing efficacy but possibly also toxicity of this drug.

中文翻译：

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P-糖蛋白（P-GP / ABCB1）和乳腺癌抗性蛋白（BCRP / ABCG2）限制了Ponatinib及其活性代谢产物N-去甲基Ponatinib的脑蓄积

Ponatinib是一种口服BCR-ABL1抑制剂，用于治疗携带费城染色体的晚期白血病，特别是含有T315I突变的突变，可产生对先前批准的BCR-ABL1抑制剂的耐药性。使用体外转运试验和基因敲除小鼠模型，我们调查了多药外排转运蛋白ABCB1和ABCG2是否转运ponatinib以及它们或药物代谢酶CYP3A是否会影响ponatinib及其活性N-去甲基代谢产物的口服有效性和脑蓄积性（DMP）。体外，小鼠Abcg2和人ABCB1适度运输了ponatinib。在小鼠中，Abcb1和Abcg2均显着限制了ponatinib和DMP的脑蓄积，但没有ponatinib的口服有效性。Abcg2缺乏症使DMP血浆水平增加约3倍。Cyp3a缺乏症会使ponatinib血浆AUC升高1.4倍。我们的结果表明，在ponatinib治疗期间对ABCG2和ABCB1的药理抑制作用可能有益于位于完整血脑屏障后或在恶性细胞中大量表达这些转运蛋白的脑（微）转移患者。CYP3A抑制剂可能会增加ponatinib的口服利用率，从而增强该药的疗效，但也可能会增加该药的毒性。