Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Mol Pharm. 2012 Nov 5;9(11):3236-45. doi: 10.1021/mp3003144. Epub 2012 Oct 18.
Vemurafenib (PLX4032) is a novel tyrosine kinase inhibitor that has clinical efficacy against metastatic melanoma harboring a BRAF(V600E) mutation. We aimed to establish whether oral availability and brain penetration of vemurafenib could be restricted by the multidrug efflux transporters P-glycoprotein (P-gp/ABCB1) and breast cancer resistance protein (BCRP/ABCG2), as these might limit therapeutic efficacy, especially against brain metastases. In vitro, vemurafenib was efficiently transported by both human ABCB1 and ABCG2, and very efficiently by mouse Abcg2, but not by mouse Abcc2. Upon oral administration of vemurafenib (5 mg/kg), Abcb1a/1b(-/-) mice had a 1.6-fold increased, Abcg2(-/-) mice a 2.3-fold increased, and Abcb1a/1b(-/-);Abcg2(-/-) mice a 6.6-fold increased plasma AUC, respectively, compared to wild-type (WT) mice, indicating a marked and additive role of these transporters in limiting vemurafenib oral availability. Brain-to-plasma ratios of vemurafenib (oral, 25 mg/kg) were not increased in Abcg2(-/-) mice, only 1.7-fold in Abcb1a/1b(-/-) mice, but 21.4-fold in Abcb1a/1b(-/-);Abcg2(-/-) mice, indicating pronounced overlapping functions of these transporters in reducing vemurafenib brain accumulation. Oral coadministration of the dual ABCB1 and ABCG2 inhibitor elacridar almost completely eliminated the roles of Abcb1 and Abcg2 in restricting oral availability and brain accumulation of vemurafenib. As predicted by previously described pharmacokinetic modeling, halving the amount of active efflux transport at the WT blood-brain barrier by testing heterozygous Abcb1a/1b(+/-);Abcg2(+/-) mice had little impact on vemurafenib brain accumulation. Our data suggest that elacridar coadministration may be considered to improve the therapeutic efficacy of vemurafenib, especially for brain metastases located behind a functional blood-brain barrier.
维莫非尼（PLX4032）是一种新型的酪氨酸激酶抑制剂，对携带 BRAF(V600E)突变的转移性黑色素瘤具有临床疗效。我们旨在确定维莫非尼的口服生物利用度和脑穿透性是否会受到多药外排转运蛋白 P 糖蛋白（P-gp/ABCB1）和乳腺癌耐药蛋白（BCRP/ABCG2）的限制，因为这些因素可能会限制治疗效果，尤其是对脑转移瘤的治疗效果。在体外，维莫非尼被人 ABCB1 和 ABCG2 有效转运，被小鼠 Abcg2 非常有效转运，但不被小鼠 Abcc2 转运。口服维莫非尼（5mg/kg）后，Abcb1a/1b(-/-) 小鼠的血浆 AUC 增加了 1.6 倍，Abcg2(-/-) 小鼠增加了 2.3 倍，Abcb1a/1b(-/-);Abcg2(-/-) 小鼠增加了 6.6 倍，表明这些转运蛋白在限制维莫非尼口服生物利用度方面具有显著的加性作用。维莫非尼（口服，25mg/kg）脑/血浆比值在 Abcg2(-/-) 小鼠中没有增加，仅在 Abcb1a/1b(-/-) 小鼠中增加 1.7 倍，但在 Abcb1a/1b(-/-);Abcg2(-/-) 小鼠中增加 21.4 倍，表明这些转运蛋白在减少维莫非尼脑积聚方面具有明显的重叠功能。双重 ABCB1 和 ABCG2 抑制剂 elacridar 的口服共给药几乎完全消除了 Abcb1 和 Abcg2 在限制维莫非尼口服生物利用度和脑积聚中的作用。根据先前描述的药代动力学模型预测，通过测试杂合 Abcb1a/1b(+/-);Abcg2(+/-) 小鼠，使 WT 血脑屏障中的主动外排转运减少一半，对维莫非尼脑积聚的影响很小。我们的数据表明，联合使用 elacridar 可能被认为是提高维莫非尼的治疗效果，特别是对位于功能血脑屏障后面的脑转移瘤。
