Abcb1 and abcg2 control brain accumulation and intestinal disposition of the novel ros1/trk/alk inhibitor repotrectinib, while oatp1a/1b, abcg2, and cyp3a limit its oral availability

Wenlong Li, Rolf W. Sparidans, Maria C. Lebre, Jos H. Beijnen, Alfred H. Schinkel*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Repotrectinib shows high activity against ROS1/TRK/ALK fusion-positive cancers in pre-clinical 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 Abcb1a/1b−/− (4.1-fold) and Abcb1a/1b;Abcg2−/− (14.2-fold) compared to wild-type mice, but not in single Abcg2−/− mice. Small intestinal content recovery of repotrectinib was decreased 4.9-fold in Abcb1a/1b−/− and 13.6-fold in Abcb1a/1b;Abcg2−/− mice. Intriguingly, Abcb1a/1b;Abcg2−/− 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 Cyp3a−/− mice, repotrectinib plasma AUC0–h was 2.3-fold in-creased, 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.

Original languageEnglish
Article number1761
Pages (from-to)1-17
JournalPharmaceutics
Volume13
Issue number11
DOIs
Publication statusPublished - Nov 2021

Bibliographical note

Funding Information:
This work was funded in part by the China Scholarship Council (CSC Scholarship No. 201606220081 to W. Li).

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Funding

This work was funded in part by the China Scholarship Council (CSC Scholarship No. 201606220081 to W. Li).

Keywords

  • Brain accumulation
  • Breast cancer resistance protein
  • Cytochrome P450-3A
  • Oral availability
  • Organic anion transporting polypeptides
  • P-glycoprotein
  • Repotrectinib (TPX-0005)

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