Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Int J Cancer. 2012 Jan 1;130(1):223-33. doi: 10.1002/ijc.26000. Epub 2011 Apr 7.
Sunitinib is an orally active, multitargeted tyrosine kinase inhibitor which has been used for the treatment of metastatic renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors. We aimed to investigate the in vivo roles of the ATP-binding cassette drug efflux transporters ABCB1 and ABCG2 in plasma pharmacokinetics and brain accumulation of oral sunitinib, and the feasibility of improving sunitinib kinetics using oral coadministration of the dual ABCB1/ABCG2 inhibitor elacridar. We used in vitro transport assays and Abcb1a/1b(-/-) , Abcg2(-/-) and Abcb1a/1b/Abcg2(-/-) mice to study the roles of ABCB1 and ABCG2 in sunitinib disposition. In vitro, sunitinib was a good substrate of murine (mu)ABCG2 and a moderate substrate of human (hu)ABCB1 and huABCG2. In vivo, the systemic exposure of sunitinib after oral dosing (10 mg kg(-1) ) was unchanged when muABCB1 and/or muABCG2 were absent. Brain accumulation of sunitinib was markedly (23-fold) increased in Abcb1a/b/Abcg2(-/-) mice, but only slightly (2.3-fold) in Abcb1a/b(-/-) mice, and not in Abcg2(-/-) mice. Importantly, a clinically realistic coadministration of oral elacridar and oral sunitinib to wild-type mice resulted in markedly increased sunitinib brain accumulation, equaling levels in Abcb1a/1b/Abcg2(-/-) mice. This indicates complete inhibition of the blood-brain barrier (BBB) transporters. High-dose intravenous sunitinib could saturate BBB muABCG2, but not muABCB1A, illustrating a dose-dependent relative impact of the BBB transporters. Brain accumulation of sunitinib is effectively restricted by both muABCB1 and muABCG2 activity. Complete inhibition of both transporters, leading to markedly increased brain accumulation of sunitinib, is feasible and safe with a clinically realistic oral elacridar/sunitinib coadministration.
舒尼替尼是一种口服活性、多靶点酪氨酸激酶抑制剂，已被用于治疗转移性肾细胞癌和伊马替尼耐药胃肠道间质瘤。我们旨在研究 ATP 结合盒药物外排转运体 ABCB1 和 ABCG2 在口服舒尼替尼的血浆药代动力学和脑内蓄积中的体内作用，以及使用口服双重 ABCB1/ABCG2 抑制剂埃拉西达提高舒尼替尼药代动力学的可行性。我们使用体外转运实验和 Abcb1a/1b(-/-)、Abcg2(-/-)和 Abcb1a/1b/Abcg2(-/-) 小鼠来研究 ABCB1 和 ABCG2 在舒尼替尼处置中的作用。在体外，舒尼替尼是鼠源（mu）ABCG2 的良好底物，也是人源（hu）ABCB1 和 huABCG2 的中等底物。在体内，当不存在 muABCB1 和/或 muABCG2 时，口服给药（10 mg/kg）后舒尼替尼的全身暴露保持不变。舒尼替尼在 Abcb1a/b/Abcg2(-/-) 小鼠中的脑内蓄积显著增加（23 倍），但在 Abcb1a/b(-/-) 小鼠中仅略有增加（2.3 倍），而在 Abcg2(-/-) 小鼠中没有增加。重要的是，临床合理的口服埃拉西达和口服舒尼替尼联合给药可使野生型小鼠的舒尼替尼脑内蓄积显著增加，与 Abcb1a/1b/Abcg2(-/-) 小鼠相当。这表明完全抑制了血脑屏障（BBB）转运体。高剂量静脉内舒尼替尼可使 BBB muABCG2 饱和，但不能使 muABCB1A 饱和，这表明 BBB 转运体的影响具有剂量依赖性。舒尼替尼的脑内蓄积受到 muABCB1 和 muABCG2 活性的有效限制。通过临床合理的口服埃拉西达/舒尼替尼联合给药，完全抑制两种转运体，可显著增加舒尼替尼的脑内蓄积，是可行且安全的。
