Pharmaceutical Research

, Volume 32, Issue 7, pp 2205–2216 | Cite as

Brain and Testis Accumulation of Regorafenib is Restricted by Breast Cancer Resistance Protein (BCRP/ABCG2) and P-glycoprotein (P-GP/ABCB1)

  • Anita Kort
  • Selvi Durmus
  • Rolf W. Sparidans
  • Els Wagenaar
  • Jos H. Beijnen
  • Alfred H. Schinkel
Research Paper
First Online:
Received:
Accepted:

Abstract

Purpose

Regorafenib is a novel multikinase inhibitor, currently approved for the treatment of metastasized colorectal cancer and advanced gastrointestinal stromal tumors. We investigated whether regorafenib is a substrate for the multidrug efflux transporters ABCG2 and ABCB1 and whether oral availability, brain and testis accumulation of regorafenib and its active metabolites are influenced by these transporters.

Methods

We used in vitro transport assays to assess human (h)ABCB1- or hABCG2- or murine (m)Abcg2-mediated active transport at high and low concentrations of regorafenib. To study the single and combined roles of Abcg2 and Abcb1a/1b in oral regorafenib disposition and the impact of Cyp3a-mediated metabolism, we used appropriate knockout mouse strains.

Results

Regorafenib was transported well by mAbcg2 and hABCG2 and modestly by hABCB1 in vitro. Abcg2 and to a lesser extent Abcb1a/1b limited brain and testis accumulation of regorafenib and metabolite M2 (brain only) in mice. Regorafenib oral availability was not increased in Abcg2 -/- ;Abcb1a/1b -/- mice. Up till 2 h, metabolite M5 was undetectable in plasma and organs.

Conclusions

Brain and testis accumulation of regorafenib and brain accumulation of metabolite M2 are restricted by Abcg2 and Abcb1a/1b. Inhibition of these transporters may be of clinical relevance for patients with brain (micro)metastases positioned behind an intact blood–brain barrier.

KEY WORDS

ABCB1 ABCG2 brain accumulation regorafenib testis accumulation 

ABBREVIATIONS

ABC

ATP-binding cassette

AUC

Area under the plasma concentration-time curve

BBB

Blood–brain barrier

BCRP

Breast cancer resistance protein

BTB

Blood-testis barrier

Cmax

Maximum drug concentration in plasma

CNS

Central nervous system

GIST

Gastrointestinal stromal tumors

LLOQ

Lower limit of quantitation

LOD

Lower limit of detection

P-gp

P-glycoprotein

SD

Standard deviation

TKI

Tyrosine kinase inhibitor

Tmax

Time after administration of a drug to reach maximum plasma concentration

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Notes

ACKNOWLEDGMENTS AND DISCLOSURES

The research group of A.H. Schinkel receives revenue from commercial distribution of some of the mouse strains used in this study.

Anita Kort and Selvi Durmus contributed equally.

Supplementary material

11095_2014_1609_MOESM1_ESM.docx (3 mb)
Supplementary Materials (DOCX 2.98 mb)

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Anita Kort
    • 1
    • 3
  • Selvi Durmus
    • 1
  • Rolf W. Sparidans
    • 2
  • Els Wagenaar
    • 1
  • Jos H. Beijnen
    • 2
    • 3
    • 4
  • Alfred H. Schinkel
    • 1
  1. 1.Division of Molecular OncologyThe Netherlands Cancer InstituteAmsterdamThe Netherlands
  2. 2.Division of Pharmacoepidemiology & Clinical Pharmacology Department of Pharmaceutical Sciences, Faculty of ScienceUtrecht UniversityUtrechtThe Netherlands
  3. 3.Department of Pharmacy & PharmacologyThe Netherlands Cancer Institute/ Slotervaart HospitalAmsterdamThe Netherlands
  4. 4.Department of Clinical PharmacologyThe Netherlands Cancer InstituteAmsterdamThe Netherlands

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