A Proof-of-Concept Study to Inhibit ABCG2- and ABCB1-Mediated Efflux Transport at the Human Blood-Brain Barrier

Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine
Martin BauerOliver Langer

Abstract

The adenosine triphosphate-binding cassette transporters P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) are 2 efflux transporters at the blood-brain barrier (BBB) that effectively restrict brain distribution of dual ABCB1/ABCG2 substrate drugs, such as tyrosine kinase inhibitors. Pharmacologic inhibition of ABCB1/ABCG2 may improve the efficacy of dual-substrate drugs for treatment of brain tumors, but no marketed ABCB1/ABCG2 inhibitors are currently available. In the present study, we examined the potential of supratherapeutic-dose oral erlotinib to inhibit ABCB1/ABCG2 activity at the human BBB. Methods: Healthy men underwent 2 consecutive PET scans with 11C-erlotinib: a baseline scan and a second scan either with concurrent intravenous infusion of the ABCB1 inhibitor tariquidar (3.75 mg/min, n = 5) or after oral intake of single ascending doses of erlotinib (300 mg, n = 7; 650 mg, n = 8; or 1,000 mg, n = 2). Results: Although tariquidar administration had no effect on 11C-erlotinib brain distribution, oral erlotinib led, at the 650-mg dose, to significant increases in volume of distribution (23% ± 13%, P = 0.008), influx rate constant of radioactivity from plasma into brain (58% ± 26%, P = 0.008), and area...Continue Reading

References

Sep 1, 1990·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·J LoganS J Gatley
Sep 11, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Paul R LockmanQuentin R Smith
Feb 5, 2011·Journal of Neurochemistry·Yasuo UchidaTetsuya Terasaki
Jun 17, 2011·Expert Reviews in Molecular Medicine·Sagar AgarwalWilliam F Elmquist
Aug 11, 2011·Current Pharmaceutical Design·Sagar AgarwalBjörn Bauer
Sep 28, 2012·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Sagar AgarwalWilliam F Elmquist
Nov 9, 2012·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Idris BahceN Harry Hendrikse
Jul 9, 2013·Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine·Martin BauerOliver Langer
Dec 17, 2014·Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine·William C KreislRobert B Innis
Feb 3, 2015·Advances in Cancer Research·Selvi DurmusAlfred H Schinkel
Feb 12, 2015·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Martin BauerOliver Langer
Mar 21, 2015·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·O van TellingenH E de Vries
Sep 12, 2015·Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine·Alexander TraxlOliver Langer
Feb 6, 2016·Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine·Maqsood YaqubAdriaan A Lammertsma
Jul 16, 2016·Biopharmaceutics & Drug Disposition·Ronilda D'CunhaGuohua An
Aug 6, 2016·Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine·Nicolas TournierOliver Langer
Sep 25, 2017·Clinical Pharmacology and Therapeutics·Martin BauerOliver Langer
Nov 28, 2017·Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine·Remy B VerheijenNeeltje Steeghs
Jan 3, 2018·Drug Delivery and Translational Research·Sébastien GoutalNicolas Tournier
Jun 1, 2018·Neoplasia : an International Journal for Oncology Research·Mark C de GooijerOlaf van Tellingen

❮ Previous
Next ❯

Citations

Oct 22, 2020·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Nicolas TournierOliver Langer
Oct 11, 2020·Molecular Therapy : the Journal of the American Society of Gene Therapy·Torayuki OkuyamaYuji Sato
Feb 28, 2020·European Journal of Medicinal Chemistry·Frauke AntoniGünther Bernhardt
Apr 4, 2021·International Journal of Molecular Sciences·Ji HeYan Li
Oct 6, 2019·Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine·Martin BauerOliver Langer
Oct 6, 2019·Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine·Eveline A van de StadtN H Hendrikse

❮ Previous
Next ❯

Related Concepts

Related Feeds

Blood Brain Barrier

The blood brain barrier is a border that separates blood from cerebrospinal fluid. Discover the latest search on this highly selective semipermeable membrane here.

Blood-Brain Barrier Transport in Neurodegeneration

The blood brain barrier is important for regulating the movement of biomolecules in and out of the brain. For example, membrane transporters in the blood brain barrier can be essential for regulating drug movement and dysregulation of these processes may play a role in neurodegeneration. This feed follows the latest research on this topic.

Blood Brain Barrier Regulation in Health & Disease

The blood brain barrier is essential in regulating the movement of molecules and substances in and out of the brain. Disruption to the blood brain barrier and changes in permeability allow pathogens and inflammatory molecules to cross the barrier and may play a part in the pathogenesis of neurodegenerative disorders. Here is the latest research in this field.

Blood Brain Barrier Chips

The blood brain barrier (BBB) is comprised of endothelial cells that regulate the influx and outflux of plasma concentrations. Lab-on-a-chip devices allow scientists to model diseases and mechanisms such as the passage of therapeutic antibodies across the BBB. Discover the latest research on BBB chips here.