Ibrutinib (Imbruvica), an oral tyrosine kinase inhibitor (TKI) approved for treatment of B-cell malignancies, irreversibly inhibits the Bruton’s tyrosine kinase (BTK). Its abundant metabolite, dihydrodiol-ibrutinib (ibrutinib-DiOH), which is primarily formed by CYP3A, has a 10-fold reduced BTK inhibitory activity. Using in vitro transport assays and genetically modified mouse models, we investigated whether the multidrug efflux transporters ABCB1 and ABCG2 and the multidrug-metabolizing CYP3A enzyme family can affect the oral bioavailability and tissue disposition of ibrutinib and ibrutinib-DiOH. In vitro, ibrutinib was transported moderately by human ABCB1 and mouse Abcg2 but not detectably by human ABCG2. In mice, Abcb1 markedly restricted the brain penetration of ibrutinib and ibrutinib-DiOH, either alone or in combination with Abcg2, resulting in 4.5- and 5.9-fold increases in ibrutinib brain-to-plasma ratios in Abcb1a/1b^–/– and Abcb1a/1b;Abcg2^–/– mice relative to wild-type mice. Abcb1 and/or Abcg2 did not obviously restrict ibrutinib oral bioavailability, but Cyp3a deficiency increased the ibrutinib plasma AUC by 9.7-fold compared to wild-type mice. This increase was mostly reversed (5.1-fold reduction) by transgenic human CYP3A4 overexpression, with roughly equal contributions of intestinal and hepatic CYP3A4 metabolism. Our results suggest that pharmacological inhibition of ABCB1 during ibrutinib therapy might benefit patients with malignancies or (micro)metastases positioned behind an intact blood-brain barrier, or with substantial expression of this transporter in the malignant cells. Moreover, given the strong in vivo impact of CYP3A, inhibitors or inducers of this enzyme family will likely strongly affect ibrutinib oral bioavailability and, thus, its therapeutic efficacy, as well as its toxicity risks.

中文翻译：

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P-糖蛋白（MDR1 / ABCB1）限制了Bruton酪氨酸激酶抑制剂依鲁替尼的脑渗透，而细胞色素P450-3A（CYP3A）限制了其口服生物利用度

依鲁替尼（Imbruvica）是一种经批准可用于治疗B细胞恶性肿瘤的口服酪氨酸激酶抑制剂（TKI），可逆地抑制Bruton酪氨酸激酶（BTK）。其主要由CYP3A形成的丰富代谢产物二氢二醇-依鲁替尼（ibrutinib-DiOH）的BTK抑制活性降低了10倍。使用体外转运测定法和基因修饰的小鼠模型，我们调查了多药外排转运蛋白ABCB1和ABCG2以及多药代谢的CYP3A酶家族是否会影响ibrutinib和ibrutinib-DiOH的口服生物利用度和组织处置。在体外，依鲁替尼被人ABCB1和小鼠Abcg2适度转运，但未被人ABCG2检测。在小鼠中，单独或与Abcg2联合使用，Abcb1显着限制了ibrutinib和ibrutinib-DiOH的脑部渗透，^{– / –}和Abcb1a / 1b; Abcg2 ^{– / –}小鼠相对于野生型小鼠。Abcb1和/或Abcg2没有明显限制依鲁替尼的口服生物利用度，但与野生型小鼠相比，Cyp3a缺乏使依鲁替尼的血浆AUC升高了9.7倍。转基因人类CYP3A4的过量表达使这种增加大部分被逆转（减少了5.1倍），肠和肝CYP3A4代谢的贡献大致相等。我们的结果表明，依鲁替尼治疗期间对ABCB1的药理学抑制作用可能有益于位于完整血脑屏障后的恶性肿瘤或（微小）转移灶，或该转运蛋白在恶性细胞中大量表达。此外，由于CYP3A在体内具有强烈的影响，因此该酶家族的抑制剂或诱导剂可能会强烈影响依鲁替尼的口服生物利用度，从而影响其治疗效果，