P-Glycoprotein (ABCB1/MDR1) and BCRP (ABCG2) Limit Brain Accumulation and Cytochrome P450-3A (CYP3A) Restricts Oral Exposure of the RET Inhibitor Selpercatinib (RETEVMO)

Selpercatinib is a targeted, FDA-approved, oral, small-molecule inhibitor for the treatment of rearranged during transfection (RET) proto-oncogene mutation-positive cancer. Using genetically modified mouse models, we investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, the OA...

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Autores principales:	Yaogeng Wang, Rolf W. Sparidans, Sander Potters, Rahime Şentürk, Maria C. Lebre, Jos H. Beijnen, Alfred H. Schinkel
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	selpercatinib cytochrome P450-3A oral exposure rearranged during transfection (RET) receptor kinase Slco1a/1b p-glycoprotein/ABCB1 Medicine R Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/a3ac2265932f41afa84cd9b41d33fe43
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spelling	oai:doaj.org-article:a3ac2265932f41afa84cd9b41d33fe432021-11-25T18:39:14ZP-Glycoprotein (ABCB1/MDR1) and BCRP (ABCG2) Limit Brain Accumulation and Cytochrome P450-3A (CYP3A) Restricts Oral Exposure of the RET Inhibitor Selpercatinib (RETEVMO)10.3390/ph141110871424-8247https://doaj.org/article/a3ac2265932f41afa84cd9b41d33fe432021-10-01T00:00:00Zhttps://www.mdpi.com/1424-8247/14/11/1087https://doaj.org/toc/1424-8247Selpercatinib is a targeted, FDA-approved, oral, small-molecule inhibitor for the treatment of rearranged during transfection (RET) proto-oncogene mutation-positive 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 selpercatinib pharmacokinetics. Selpercatinib was efficiently transported by hABCB1 and mAbcg2, but not hABCG2, and was not a substrate of human OATP1A2, -1B1 or -1B3 in vitro. In vivo, brain and testis penetration were increased by 3.0- and 2.7-fold in <i>Abcb1a/1b<sup>-/-</sup></i> mice and by 6.2- and 6.4-fold in <i>Abcb1a/1b;Abcg2<sup>-/-</sup></i> mice, respectively. Oatp1a/1b deficiency did not alter selpercatinib pharmacokinetics. The ABCB1/ABCG2 inhibitor elacridar boosted selpercatinib brain penetration in wild-type mice to the levels seen in <i>Abcb1a/1b;Abcg2<sup>-/-</sup></i> mice. <i>Cyp3a<sup>-/-</sup></i> mice showed a 1.4-fold higher plasma AUC<sub>0–4h</sub> than wild-type mice, which was then 1.6-fold decreased upon transgenic overexpression of human CYP3A4 in liver and intestine. In summary, ABCG2, and especially ABCB1, limit brain and testis penetration of selpercatinib. Elacridar coadministration could mostly reverse these effects, without causing acute toxicity. CYP3A-mediated metabolism can limit selpercatinib oral exposure and hence its tissue concentrations. These insights may be useful in the further clinical development of selpercatinib.Yaogeng WangRolf W. SparidansSander PottersRahime ŞentürkMaria C. LebreJos H. BeijnenAlfred H. SchinkelMDPI AGarticleselpercatinibcytochrome P450-3Aoral exposurerearranged during transfection (RET) receptor kinaseSlco1a/1bp-glycoprotein/ABCB1MedicineRPharmacy and materia medicaRS1-441ENPharmaceuticals, Vol 14, Iss 1087, p 1087 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	selpercatinib cytochrome P450-3A oral exposure rearranged during transfection (RET) receptor kinase Slco1a/1b p-glycoprotein/ABCB1 Medicine R Pharmacy and materia medica RS1-441
spellingShingle	selpercatinib cytochrome P450-3A oral exposure rearranged during transfection (RET) receptor kinase Slco1a/1b p-glycoprotein/ABCB1 Medicine R Pharmacy and materia medica RS1-441 Yaogeng Wang Rolf W. Sparidans Sander Potters Rahime Şentürk Maria C. Lebre Jos H. Beijnen Alfred H. Schinkel P-Glycoprotein (ABCB1/MDR1) and BCRP (ABCG2) Limit Brain Accumulation and Cytochrome P450-3A (CYP3A) Restricts Oral Exposure of the RET Inhibitor Selpercatinib (RETEVMO)
description	Selpercatinib is a targeted, FDA-approved, oral, small-molecule inhibitor for the treatment of rearranged during transfection (RET) proto-oncogene mutation-positive 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 selpercatinib pharmacokinetics. Selpercatinib was efficiently transported by hABCB1 and mAbcg2, but not hABCG2, and was not a substrate of human OATP1A2, -1B1 or -1B3 in vitro. In vivo, brain and testis penetration were increased by 3.0- and 2.7-fold in <i>Abcb1a/1b<sup>-/-</sup></i> mice and by 6.2- and 6.4-fold in <i>Abcb1a/1b;Abcg2<sup>-/-</sup></i> mice, respectively. Oatp1a/1b deficiency did not alter selpercatinib pharmacokinetics. The ABCB1/ABCG2 inhibitor elacridar boosted selpercatinib brain penetration in wild-type mice to the levels seen in <i>Abcb1a/1b;Abcg2<sup>-/-</sup></i> mice. <i>Cyp3a<sup>-/-</sup></i> mice showed a 1.4-fold higher plasma AUC<sub>0–4h</sub> than wild-type mice, which was then 1.6-fold decreased upon transgenic overexpression of human CYP3A4 in liver and intestine. In summary, ABCG2, and especially ABCB1, limit brain and testis penetration of selpercatinib. Elacridar coadministration could mostly reverse these effects, without causing acute toxicity. CYP3A-mediated metabolism can limit selpercatinib oral exposure and hence its tissue concentrations. These insights may be useful in the further clinical development of selpercatinib.
format	article
author	Yaogeng Wang Rolf W. Sparidans Sander Potters Rahime Şentürk Maria C. Lebre Jos H. Beijnen Alfred H. Schinkel
author_facet	Yaogeng Wang Rolf W. Sparidans Sander Potters Rahime Şentürk Maria C. Lebre Jos H. Beijnen Alfred H. Schinkel
author_sort	Yaogeng Wang
title	P-Glycoprotein (ABCB1/MDR1) and BCRP (ABCG2) Limit Brain Accumulation and Cytochrome P450-3A (CYP3A) Restricts Oral Exposure of the RET Inhibitor Selpercatinib (RETEVMO)
title_short	P-Glycoprotein (ABCB1/MDR1) and BCRP (ABCG2) Limit Brain Accumulation and Cytochrome P450-3A (CYP3A) Restricts Oral Exposure of the RET Inhibitor Selpercatinib (RETEVMO)
title_full	P-Glycoprotein (ABCB1/MDR1) and BCRP (ABCG2) Limit Brain Accumulation and Cytochrome P450-3A (CYP3A) Restricts Oral Exposure of the RET Inhibitor Selpercatinib (RETEVMO)
title_fullStr	P-Glycoprotein (ABCB1/MDR1) and BCRP (ABCG2) Limit Brain Accumulation and Cytochrome P450-3A (CYP3A) Restricts Oral Exposure of the RET Inhibitor Selpercatinib (RETEVMO)
title_full_unstemmed	P-Glycoprotein (ABCB1/MDR1) and BCRP (ABCG2) Limit Brain Accumulation and Cytochrome P450-3A (CYP3A) Restricts Oral Exposure of the RET Inhibitor Selpercatinib (RETEVMO)
title_sort	p-glycoprotein (abcb1/mdr1) and bcrp (abcg2) limit brain accumulation and cytochrome p450-3a (cyp3a) restricts oral exposure of the ret inhibitor selpercatinib (retevmo)
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/a3ac2265932f41afa84cd9b41d33fe43
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P-Glycoprotein (ABCB1/MDR1) and BCRP (ABCG2) Limit Brain Accumulation and Cytochrome P450-3A (CYP3A) Restricts Oral Exposure of the RET Inhibitor Selpercatinib (RETEVMO)

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