1. Academic Validation
  2. ABCB1 and ABCG2, but not CYP3A4 limit oral availability and brain accumulation of the RET inhibitor pralsetinib

ABCB1 and ABCG2, but not CYP3A4 limit oral availability and brain accumulation of the RET inhibitor pralsetinib

  • Pharmacol Res. 2021 Oct;172:105850. doi: 10.1016/j.phrs.2021.105850.
Yaogeng Wang 1 Rolf W Sparidans 2 Sander Potters 3 Maria C Lebre 1 Jos H Beijnen 4 Alfred H Schinkel 5
Affiliations

Affiliations

  • 1 The Netherlands Cancer Institute, Division of Pharmacology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
  • 2 Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacology, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
  • 3 Leiden university, Faculty of Science, Leiden Academic Centre for Drug Research (LACDR), Einsteinweg 55, 2300 RA Leiden, The Netherlands.
  • 4 The Netherlands Cancer Institute, Division of Pharmacology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacology, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands; The Netherlands Cancer Institute, Department of Pharmacy & Pharmacology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
  • 5 The Netherlands Cancer Institute, Division of Pharmacology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Electronic address: a.schinkel@nki.nl.
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 transport was assessed. In vivo, pralsetinib (10 mg/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.

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).

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-112301
    99.98%, RET抑制剂
    RET