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Breast cancer resistance protein and P-glycoprotein limit sorafenib brain accumulation

Jurjen S Lagas1, Robert A B van Waterschoot, Rolf W Sparidans

  • 1Division of Molecular Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.

Molecular Cancer Therapeutics
|January 28, 2010
PubMed

Insights

Sorafenib brain accumulation is mainly limited by ABCG2 transporter, not P-gp. Inhibiting ABCG2 may improve sorafenib

Area of Science:

  • Pharmacology and Toxicology
  • Neuroscience
  • Cancer Research

Background:

  • Sorafenib is an orally active multikinase inhibitor used for advanced renal cell carcinoma and hepatocellular carcinoma.
  • Understanding drug transport across the blood-brain barrier (BBB) is crucial for treating central nervous system (CNS) cancers.
  • P-glycoprotein (P-gp/ABCB1) and ABCG2 (breast cancer resistance protein) are key efflux transporters at the BBB.

Purpose of the Study:

  • To investigate the role of P-gp and ABCG2 in restricting sorafenib brain accumulation.
  • To compare the contribution of ABCG2 versus P-gp in limiting sorafenib CNS entry.

Main Methods:

  • In vitro transport assays using MDCK-II cells expressing human P-gp or ABCG2, and murine Abcg2.
  • Oral administration of sorafenib to wild-type, Abcb1a/1b(-/-), Abcg2(-/-), and double knockout mice.
  • Pharmacokinetic analysis of plasma and brain sorafenib concentrations.
  • Assessment of brain accumulation with co-administration of elacridar, a dual P-gp/ABCG2 inhibitor.

Main Results:

  • Sorafenib showed moderate transport by P-gp but was more efficiently transported by ABCG2 and Abcg2 in vitro.
  • Systemic exposure was similar across all mouse strains, but brain accumulation was significantly increased in Abcg2(-/-) and double knockout mice.
  • Co-administration of elacridar in wild-type mice mimicked the brain accumulation seen in double knockout mice, indicating ABCG2's dominant role.

Conclusions:

  • ABCG2, not P-gp, is the primary transporter restricting sorafenib brain accumulation.
  • This finding contrasts with previous studies where P-gp was considered dominant at the BBB.
  • Targeting ABCG2, potentially with dual inhibitors, could enhance sorafenib CNS penetration for treating CNS relapses in cancer patients.

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