The Netherlands Cancer Institute, Division of Pharmacology, Amsterdam, The Netherlands.
The Netherlands Cancer Institute, Department of Pharmacy & Pharmacology, Amsterdam, The Netherlands.
Int J Cancer. 2020 Mar 15;146(6):1631-1642. doi: 10.1002/ijc.32568. Epub 2019 Jul 15.
Galunisertib (LY2157299), a promising small-molecule inhibitor of the transforming growth factor-beta (TGF-β) receptor, is currently in mono- and combination therapy trials for various cancers including glioblastoma, hepatocellular carcinoma and breast cancer. Using genetically modified mouse models, we investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, the OATP1A/1B uptake transporters and the drug-metabolizing CYP3A complex in galunisertib pharmacokinetics. In vitro, galunisertib was vigorously transported by human ABCB1, and moderately by mouse Abcg2. Orally administered galunisertib (20 mg/kg) was very rapidly absorbed. Galunisertib brain-to-plasma ratios were increased by ~24-fold in Abcb1a/1b and Abcb1a/1b;Abcg2 mice compared to wild-type mice, but not in single Abcg2 mice, whereas galunisertib oral availability was not markedly affected. However, recovery of galunisertib in the small intestinal lumen was strongly reduced in Abcb1a/1b and Abcb1a/1b;Abcg2 mice. Oral coadministration of the ABCB1/ABCG2 inhibitor elacridar boosted galunisertib brain accumulation in wild-type mice to equal the levels seen in Abcb1a/1b;Abcg2 mice. Oatp1a/1b deficiency did not alter oral galunisertib pharmacokinetics or liver distribution. Cyp3a mice showed a 1.9-fold higher plasma AUC than wild-type mice, but this difference disappeared over 8 hr. Also, transgenic human CYP3A4 overexpression did not significantly alter oral galunisertib pharmacokinetics. Abcb1 thus markedly restricts galunisertib brain penetration and affects its intestinal disposition, possibly through biliary excretion. Elacridar coadministration could fully inhibit both processes, without causing acute toxicity. Moreover, mouse Cyp3a, but not human CYP3A4, may eliminate galunisertib at high plasma concentrations. These insights may help to guide the further clinical development and application of galunisertib.
Galunisertib（LY2157299）是一种有前途的转化生长因子-β（TGF-β）受体小分子抑制剂，目前正在针对包括胶质母细胞瘤、肝细胞癌和乳腺癌在内的各种癌症进行单药和联合治疗试验。我们使用基因修饰的小鼠模型研究了多药外排转运蛋白 ABCB1 和 ABCG2、OATP1A/1B 摄取转运蛋白和药物代谢 CYP3A 复合物在 galunisertib 药代动力学中的作用。在体外，galunisertib 被人 ABCB1 强烈转运，被鼠 Abcg2 适度转运。口服给予 20mg/kg 的 galunisertib 后被迅速吸收。与野生型小鼠相比，Abcb1a/1b 和 Abcb1a/1b;Abcg2 小鼠的 galunisertib 脑-血浆比增加了约 24 倍，但在单 Abcg2 小鼠中则没有，而 galunisertib 的口服生物利用度没有明显受到影响。然而，在 Abcb1a/1b 和 Abcb1a/1b;Abcg2 小鼠中，回肠腔中小肠内 galunisertib 的回收明显减少。ABCBl/ABCG2 抑制剂 elacridar 的口服共给予将野生型小鼠的 galunisertib 脑积累量提高到与 Abcb1a/1b;Abcg2 小鼠相同的水平。Oatp1a/1b 缺乏并未改变口服 galunisertib 的药代动力学或肝脏分布。Cyp3a 小鼠的血浆 AUC 比野生型小鼠高 1.9 倍，但 8 小时后这一差异消失。此外，转基因人 CYP3A4 的过表达也没有显著改变口服 galunisertib 的药代动力学。Abcb1 因此显著限制了 galunisertib 进入大脑，并影响其肠道处置，可能通过胆汁排泄。Elacridar 的共给予可以完全抑制这两个过程，而不会引起急性毒性。此外，可能是小鼠 Cyp3a 而不是人 CYP3A4 在高血浆浓度下消除 galunisertib。这些见解可能有助于指导 galunisertib 的进一步临床开发和应用。
