Co-administration strategy to enhance brain accumulation of vandetanib by modulating P-glycoprotein (P-gp/Abcb1) and breast cancer resistance protein (Bcrp1/Abcg2) mediated efflux with m-TOR inhibitors
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The objectives of this study were (i) to characterize the interaction of vandetanib with P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp1) in vitro and in vivo (ii) to study the modulation of P-gp and BCRP mediated efflux of vandetanib with specific transport inhibitors and m-TOR inhibitors, everolimus and temsirolimus. Cellular accumulation and bi-directional transport studies in MDCKII cell monolayers were conducted to delineate the role of efflux transporters on disposition of vandetanib. Brain distribution studies were conducted in male FVB wild-type mice with vandetanib administered intravenously either alone or in the presence of specific inhibitors and m-TOR inhibitors. In vitro studies suggested that vandetanib is a high affinity substrate of Bcrp1 but is not transported by P-gp. Interestingly, in vivo brain distribution studies in FVB wild type mice indicated that vandetanib penetration into the brain is restricted by both Bcrp1 and P-gp mediated active efflux at the blood brain barrier (BBB). Co-administration of elacridar, a dual P-gp/BCRP inhibitor increased the brain to plasma concentration ratio of vandetanib upto 5 fold. Of the two m-TOR pathway inhibitors examined; everolimus showed potent effect on modulating vandetanib brain penetration whereas no significant affect on vandetanib brain uptake was observed following temsirolimus co-administration. This finding could be clinically relevant as everolimus can provide synergistic pharmacological effect in addition to primary role of vandetanib efflux modulation at BBB for the treatment of brain tumors.
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RAD001, an FDA-approved mTORC1 inhibitor for treatment of renal cell carcinomas, has also been shown to inhibit MDR1 function in cancer cells.
“Additionally, RAD001, an FDA-approved mTORC1 inhibitor for treatment of renal cell carcinomas, has also been shown to inhibit MDR1 function in cancer cells (37).”
From The drug efflux pump MDR1 promotes intrinsic and acquired resistance to PROTACs in cancer cells (2022) · cites this paper as [37]
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The drug efflux pump MDR1 promotes intrinsic and acquired resistance to PROTACs in cancer cells
Kurimchak, A. M., Herrera-Montávez, C., Montserrat-Sangrà, S., Araiza-Olivera, D., Hu, J., Neumann-Domer, R., Kuruvilla, M., Bellacosa, A., Testa, J. R., Jin, J., et al. (2022) · Science Signaling · doi:10.1126/scisignal.abn2707 · Cited by 136 · see citing works
- Authors
- Minocha, M., Khurana, V., Qin, B., Pal, D., & Mitra, A. K.
- Affiliations
- University of Missouri–Kansas City (US)
- Corresponding author
- Mitra, Ashim K.
- Venue
- International Journal of Pharmaceutics
- Publisher
- Elsevier BV
- Published
- 2012-09
- Volume
- 434
- Issue
- 1-2
- Pages
- 306-314
- ISSN
- 0378-5173 (ISSN-L)
- PMC
- PMC3402233
- OpenAlex
- W2064808628
- Cited by
- 82
- References
- 33
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 3 · 2023: 4 · 2022: 1 · 2021: 7 · 2020: 2 · 2019: 4 · 2018: 3 · 2017: 13 · 2016: 6 · 2015: 14 · 2014: 10 · 2013: 7 · 2012: 1
- FWCI
- 5.07
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- International Journal of Pharmaceutics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (R01AI071199)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- vandetanib, P-glycoprotein, BCRP1, ABCG2, blood-brain barrier, brain penetration, efflux pumps, mTOR inhibitors, everolimus, temsirolimus, elacridar, drug-drug interactions, brain tumor therapy
- MeSH terms
- Everolimus, ATP Binding Cassette Transporter, Subfamily G, Member 2, Animals, Antineoplastic Agents, Biological Transport, Blood-Brain Barrier, Brain, Cell Line, Dogs, Drug Synergism, Male, Piperidines, Quinazolines, Tissue Distribution, ATP Binding Cassette Transporter, Subfamily B, ATP-Binding Cassette Transporters, Sirolimus, ATP Binding Cassette Transporter, Subfamily B, Member 1, Mice, TOR Serine-Threonine Kinases
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