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

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 ge...

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Autores principales:	Wenlong Li, Rolf W. Sparidans, Maria C. Lebre, Jos H. Beijnen, Alfred H. Schinkel
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	repotrectinib (TPX-0005) P-glycoprotein breast cancer resistance protein brain accumulation organic anion transporting polypeptides cytochrome P450-3A Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/96586ee99982471e86dd47f36c4d54e8
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spelling	oai:doaj.org-article:96586ee99982471e86dd47f36c4d54e82021-11-25T18:40:27ZABCB1 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 Availability10.3390/pharmaceutics131117611999-4923https://doaj.org/article/96586ee99982471e86dd47f36c4d54e82021-10-01T00:00:00Zhttps://www.mdpi.com/1999-4923/13/11/1761https://doaj.org/toc/1999-4923Repotrectinib 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 <i>Abcb1a/1b<sup>−/−</sup></i> (4.1-fold) and <i>Abcb1a/1b;Abcg2<sup>−/−</sup></i> (14.2-fold) compared to wild-type mice, but not in single <i>Abcg2<sup>−/−</sup></i> mice. Small intestinal content recovery of repotrectinib was decreased 4.9-fold in <i>Abcb1a/1b<sup>−/−</sup></i> and 13.6-fold in <i>Abcb1a/1b;Abcg2<sup>−/−</sup></i> mice. Intriguingly, <i>Abcb1a/1b;Abcg2<sup>−/−</sup></i> 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 <i>Cyp3a<sup>−/−</sup></i> mice, repotrectinib plasma AUC<sub>0–h</sub> 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.Wenlong LiRolf W. SparidansMaria C. LebreJos H. BeijnenAlfred H. SchinkelMDPI AGarticlerepotrectinib (TPX-0005)P-glycoproteinbreast cancer resistance proteinbrain accumulationorganic anion transporting polypeptidescytochrome P450-3APharmacy and materia medicaRS1-441ENPharmaceutics, Vol 13, Iss 1761, p 1761 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	repotrectinib (TPX-0005) P-glycoprotein breast cancer resistance protein brain accumulation organic anion transporting polypeptides cytochrome P450-3A Pharmacy and materia medica RS1-441
spellingShingle	repotrectinib (TPX-0005) P-glycoprotein breast cancer resistance protein brain accumulation organic anion transporting polypeptides cytochrome P450-3A Pharmacy and materia medica RS1-441 Wenlong Li Rolf W. Sparidans Maria C. Lebre Jos H. Beijnen Alfred H. Schinkel 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
description	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 <i>Abcb1a/1b<sup>−/−</sup></i> (4.1-fold) and <i>Abcb1a/1b;Abcg2<sup>−/−</sup></i> (14.2-fold) compared to wild-type mice, but not in single <i>Abcg2<sup>−/−</sup></i> mice. Small intestinal content recovery of repotrectinib was decreased 4.9-fold in <i>Abcb1a/1b<sup>−/−</sup></i> and 13.6-fold in <i>Abcb1a/1b;Abcg2<sup>−/−</sup></i> mice. Intriguingly, <i>Abcb1a/1b;Abcg2<sup>−/−</sup></i> 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 <i>Cyp3a<sup>−/−</sup></i> mice, repotrectinib plasma AUC<sub>0–h</sub> 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.
format	article
author	Wenlong Li Rolf W. Sparidans Maria C. Lebre Jos H. Beijnen Alfred H. Schinkel
author_facet	Wenlong Li Rolf W. Sparidans Maria C. Lebre Jos H. Beijnen Alfred H. Schinkel
author_sort	Wenlong Li
title	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
title_short	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
title_full	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
title_fullStr	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
title_full_unstemmed	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
title_sort	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
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/96586ee99982471e86dd47f36c4d54e8
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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

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