ABCB1 and ABCG2, but not CYP3A4 limit oral availability and brain accumulation of the RET inhibitor pralsetinib
Wang, Yaogeng; Sparidans, Rolf W; Potters, Sander; Lebre, Maria C; Beijnen, Jos H; Schinkel, Alfred H
(2021) Pharmacological Research, volume 172, pp. 1 - 12
(Article)
Abstract
BACKGROUND AND PURPOSE: Pralsetinib is an FDA-approved oral small-molecule inhibitor for treatment of rearranged during transfection (RET) proto-oncogene fusion-positive non-small cell lung cancer. We investigated how the efflux transporters ABCB1 and ABCG2, the SLCO1A/1B uptake transporters and the drug-metabolizing enzyme CYP3A influence pralsetinib pharmacokinetics. EXPERIMENTAL APPROACH: In vitro, transepithelial pralsetinib
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transport was assessed. In vivo, pralsetinib (10mg/kg) was administered orally to relevant genetically modified mouse models. Pralsetinib concentrations in cell medium, plasma samples and organ homogenates were measured using liquid chromatography-tandem mass spectrometry. KEY RESULTS: Pralsetinib was efficiently transported by human (h)ABCB1 and mouse (m)Abcg2, but not hACBG2. In vivo, mAbcb1a/1b markedly and mAbcg2 slightly limited pralsetinib brain penetration (6.3-and 1.8-fold, respectively). Testis distribution showed similar results. Abcb1a/1b;Abcg2-/- mice showed 1.5-fold higher plasma exposure, 23-fold increased brain penetration, and 4-fold reduced recovery of pralsetinib in the small intestinal content. mSlco1a/1b deficiency did not affect pralsetinib oral availability or tissue exposure. Oral coadministration of the ABCB1/ABCG2 inhibitor elacridar boosted pralsetinib plasma exposure (1.3-fold) and brain penetration (19.6-fold) in wild-type mice. Additionally, pralsetinib was a modest substrate of mCYP3A, but not of hCYP3A4, which did not noticeably restrict the oral availability or tissue distribution of pralsetinib. CONCLUSIONS AND IMPLICATIONS: SLCO1A/1B and CYP3A4 are unlikely to affect the pharmacokinetics of pralsetinib, but ABCG2 and especially ABCB1 markedly limit its brain and testis penetration, as well as oral availability. These effects are mostly reversed by oral coadministration of the ABCB1/ABCG2 inhibitor elacridar. These insights may be useful in the further clinical development of pralsetinib.
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Keywords: BCRP/ABCG2, Brain accumulation, Cabozantinib (PubChem CID: 25102847), Cytochrome P450-3A, Elacridar (PubChem CID: 119373), Oral availability, P-glycoprotein/ABCB1, Pralsetinib, Pralsetinib (PubChem CID: 129073603), Selpercatinib (PubChem CID: 134436906), Vandetanib (PubChem CID: 3081361), Zosuquidar (PubChem CID: 3036703), Pharmacology
ISSN: 1043-6618
Publisher: Academic Press Inc.
Note: Funding Information: This work was funded in part by the Chinese Scholarship Council (CSC Scholarship No. 201506240107 to Y.W.). We gratefully acknowledge Rahime ?ent?rk for the development and validation of the bioanalytical LC-MS/MS assay at the Utrecht University. Yaogeng Wang and Alfred H. Schinkel designed the study, analyzed the data and wrote the manuscript. Alfred H. Schinkel administered and supervised the project. Yaogeng Wang, Rolf W. Sparidans, and Sander Potters performed the experimental parts of the study. Maria C. Lebre contributed reagents, materials, and mice. Jos H. Beijnen and Rolf W. Sparidans supervised the bioanalytical part of the studies and checked the content and language of manuscript. All authors commented on and approved the manuscript for submission. The research group of Alfred Schinkel receives revenue from commercial distribution of some of the mouse strains used in this study. The graphical abstract was created with Biorender.com. The remaining authors declare no conflict of interest. Funding Information: This work was funded in part by the Chinese Scholarship Council (CSC Scholarship No. 201506240107 to Y.W.). We gratefully acknowledge Rahime Şentürk for the development and validation of the bioanalytical LC-MS/MS assay at the Utrecht University. Publisher Copyright: © 2021 Elsevier Ltd
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