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

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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.

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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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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.

Author information

Authors and Affiliations

  1. Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    Anita Kort, Selvi Durmus, Els Wagenaar & Alfred H. Schinkel

  2. Division of Pharmacoepidemiology & Clinical Pharmacology Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands

    Rolf W. Sparidans & Jos H. Beijnen

  3. Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute/ Slotervaart Hospital, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    Anita Kort & Jos H. Beijnen

  4. Department of Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    Jos H. Beijnen

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  1. Anita Kort
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  2. Selvi Durmus
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Correspondence to Alfred H. Schinkel.

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Kort, A., Durmus, S., Sparidans, R.W. et al. Brain and Testis Accumulation of Regorafenib is Restricted by Breast Cancer Resistance Protein (BCRP/ABCG2) and P-glycoprotein (P-GP/ABCB1). Pharm Res 32, 2205–2216 (2015). https://doi.org/10.1007/s11095-014-1609-7

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  • DOI: https://doi.org/10.1007/s11095-014-1609-7

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