Li Wenlong, Sparidans Rolf W, Lebre Maria C, Beijnen Jos H, Schinkel Alfred H
The Netherlands Cancer Institute, Division of Pharmacology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Division of Pharmacology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
Pharmaceutics. 2021 Oct 21;13(11):1761. doi: 10.3390/pharmaceutics13111761.
Repotrectinib shows high activity against ROS1/TRK/ALK fusion-positive cancers in preclinical studies. We explored the roles of multidrug efflux transporters ABCB1 and ABCG2, the OATP1A/1B uptake transporter(s), and the CYP3A complex in pharmacokinetics and tissue distribution of repotrectinib in genetically modified mouse models. In vitro, human ABCB1 and ABCG2, and mouse Abcg2 efficiently transported repotrectinib with efflux transport ratios of 13.5, 5.6, and 40, respectively. Oral repotrectinib (10 mg/kg) showed higher plasma exposures in Abcg2-deficient mouse strains. Brain-to-plasma ratios were increased in (4.1-fold) and (14.2-fold) compared to wild-type mice, but not in single mice. Small intestinal content recovery of repotrectinib was decreased 4.9-fold in and 13.6-fold in mice. Intriguingly, mice displayed transient, mild, likely CNS-localized toxicity. Oatp1a/1b deficiency caused a 2.3-fold increased oral availability and corresponding decrease in liver distribution of repotrectinib. In mice, repotrectinib plasma AUC was 2.3-fold increased, and subsequently reduced 2.0-fold in humanized CYP3A4 transgenic mice. Collectively, Abcb1 and Abcg2 restrict repotrectinib brain accumulation and possibly toxicity, and control its intestinal disposition. Abcg2 also limits repotrectinib oral availability. Oatp1a/1b mediates repotrectinib liver uptake, thus reducing its systemic exposure. Systemic exposure of repotrectinib is also substantially limited by CYP3A activity. These insights may be useful to optimize the therapeutic application of repotrectinib.
在临床前研究中，瑞波替尼对ROS1/TRK/ALK融合阳性癌症显示出高活性。我们在基因改造小鼠模型中探究了多药外排转运体ABCB1和ABCG2、OATP1A/1B摄取转运体以及CYP3A复合物在瑞波替尼药代动力学和组织分布中的作用。在体外，人ABCB1和ABCG2以及小鼠Abcg2能有效转运瑞波替尼，外排转运率分别为13.5、5.6和40。口服瑞波替尼（10毫克/千克）在Abcg2缺陷小鼠品系中显示出更高的血浆暴露量。与野生型小鼠相比，ABCG2缺陷小鼠（4.1倍）和ABCB1/ABCG2双缺陷小鼠（14.2倍）的脑血比增加，但单ABCB1缺陷小鼠未增加。瑞波替尼在ABCG2缺陷小鼠和ABCB1/ABCG2双缺陷小鼠小肠中的含量回收率分别降低了4.9倍和13.6倍。有趣的是，ABCB1/ABCG2双缺陷小鼠表现出短暂、轻微、可能局限于中枢神经系统的毒性。Oatp1a/1b缺陷导致瑞波替尼口服生物利用度增加2.3倍，肝脏分布相应减少。在ABCB1缺陷小鼠中，瑞波替尼血浆AUC增加2.3倍，随后在人源化CYP3A4转基因小鼠中降低2.0倍。总体而言，Abcb1和Abcg2限制了瑞波替尼的脑内蓄积及可能的毒性，并控制其肠道处置。Abcg2还限制了瑞波替尼的口服生物利用度。Oatp1a/1b介导瑞波替尼的肝脏摄取，从而降低其全身暴露量。瑞波替尼的全身暴露量也受到CYP3A活性的显著限制。这些见解可能有助于优化瑞波替尼的治疗应用。
