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

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.

• Authors: Anita Kort, Selvi Durmus, Rolf W Sparidans, Els Wagenaar, Jos H Beijnen, Alfred H Schinkel
• Journal: Pharmaceutical research (Pharm Res) Vol. 32 Issue 7 Pg. 2205-16 (Jul 2015) ISSN: 1573-904X [Electronic] United States
• PMID: 25563977 (Publication Type: Journal Article)

Chemical References

• ABCB1 protein, human
• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters
• Abcg2 protein, mouse
• Antineoplastic Agents
• Neoplasm Proteins
• Phenylurea Compounds
• Pyridines
• regorafenib
• Abcb1b protein, mouse

Topics

• ATP Binding Cassette Transporter, Subfamily B (genetics, metabolism)
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters (genetics, metabolism)
• Administration, Oral
• Animals
• Antineoplastic Agents (blood, metabolism, pharmacokinetics)
• Biological Transport
• Brain (metabolism)
• Dogs
• Humans
• Madin Darby Canine Kidney Cells
• Male
• Mice
• Mice, Knockout
• Neoplasm Proteins (genetics, metabolism)
• Phenylurea Compounds (blood, metabolism, pharmacokinetics)
• Pyridines (blood, metabolism, pharmacokinetics)
• Testis (metabolism)
• Tissue Distribution
• Transfection