Cargando…

Pilot PET Study to Assess the Functional Interplay Between ABCB1 and ABCG2 at the Human Blood–Brain Barrier

ABCB1 and ABCG2 work together at the blood–brain barrier (BBB) to limit brain distribution of dual ABCB1/ABCG2 substrates. In this pilot study we used positron emission tomography (PET) to assess brain distribution of two model ABCB1/ABCG2 substrates ([(11)C]elacridar and [(11)C]tariquidar) in healt...

Descripción completa

Detalles Bibliográficos
Autores principales: Bauer, M, Römermann, K, Karch, R, Wulkersdorfer, B, Stanek, J, Philippe, C, Maier‐Salamon, A, Haslacher, H, Jungbauer, C, Wadsak, W, Jäger, W, Löscher, W, Hacker, M, Zeitlinger, M, Langer, O
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979595/
https://www.ncbi.nlm.nih.gov/pubmed/26940368
http://dx.doi.org/10.1002/cpt.362
_version_ 1782447340703973376
author Bauer, M
Römermann, K
Karch, R
Wulkersdorfer, B
Stanek, J
Philippe, C
Maier‐Salamon, A
Haslacher, H
Jungbauer, C
Wadsak, W
Jäger, W
Löscher, W
Hacker, M
Zeitlinger, M
Langer, O
author_facet Bauer, M
Römermann, K
Karch, R
Wulkersdorfer, B
Stanek, J
Philippe, C
Maier‐Salamon, A
Haslacher, H
Jungbauer, C
Wadsak, W
Jäger, W
Löscher, W
Hacker, M
Zeitlinger, M
Langer, O
author_sort Bauer, M
collection PubMed
description ABCB1 and ABCG2 work together at the blood–brain barrier (BBB) to limit brain distribution of dual ABCB1/ABCG2 substrates. In this pilot study we used positron emission tomography (PET) to assess brain distribution of two model ABCB1/ABCG2 substrates ([(11)C]elacridar and [(11)C]tariquidar) in healthy subjects without (c.421CC) or with (c.421CA) the ABCG2 single‐nucleotide polymorphism (SNP) c.421C>A. Subjects underwent PET scans under conditions when ABCB1 and ABCG2 were functional and during ABCB1 inhibition with high‐dose tariquidar. In contrast to the ABCB1‐selective substrate (R)‐[(11)C]verapamil, [(11)C]elacridar and [(11)C]tariquidar showed only moderate increases in brain distribution during ABCB1 inhibition. This provides evidence for a functional interplay between ABCB1 and ABCG2 at the human BBB and suggests that both ABCB1 and ABCG2 need to be inhibited to achieve substantial increases in brain distribution of dual ABCB1/ABCG2 substrates. During ABCB1 inhibition c.421CA subjects had significantly higher increases in [(11)C]tariquidar brain distribution than c.421CC subjects, pointing to impaired cerebral ABCG2 function.
format Online
Article
Text
id pubmed-4979595
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-49795952016-08-19 Pilot PET Study to Assess the Functional Interplay Between ABCB1 and ABCG2 at the Human Blood–Brain Barrier Bauer, M Römermann, K Karch, R Wulkersdorfer, B Stanek, J Philippe, C Maier‐Salamon, A Haslacher, H Jungbauer, C Wadsak, W Jäger, W Löscher, W Hacker, M Zeitlinger, M Langer, O Clin Pharmacol Ther Clinical Trial ABCB1 and ABCG2 work together at the blood–brain barrier (BBB) to limit brain distribution of dual ABCB1/ABCG2 substrates. In this pilot study we used positron emission tomography (PET) to assess brain distribution of two model ABCB1/ABCG2 substrates ([(11)C]elacridar and [(11)C]tariquidar) in healthy subjects without (c.421CC) or with (c.421CA) the ABCG2 single‐nucleotide polymorphism (SNP) c.421C>A. Subjects underwent PET scans under conditions when ABCB1 and ABCG2 were functional and during ABCB1 inhibition with high‐dose tariquidar. In contrast to the ABCB1‐selective substrate (R)‐[(11)C]verapamil, [(11)C]elacridar and [(11)C]tariquidar showed only moderate increases in brain distribution during ABCB1 inhibition. This provides evidence for a functional interplay between ABCB1 and ABCG2 at the human BBB and suggests that both ABCB1 and ABCG2 need to be inhibited to achieve substantial increases in brain distribution of dual ABCB1/ABCG2 substrates. During ABCB1 inhibition c.421CA subjects had significantly higher increases in [(11)C]tariquidar brain distribution than c.421CC subjects, pointing to impaired cerebral ABCG2 function. John Wiley and Sons Inc. 2016-05-09 2016-08 /pmc/articles/PMC4979595/ /pubmed/26940368 http://dx.doi.org/10.1002/cpt.362 Text en © 2016, The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Clinical Trial
Bauer, M
Römermann, K
Karch, R
Wulkersdorfer, B
Stanek, J
Philippe, C
Maier‐Salamon, A
Haslacher, H
Jungbauer, C
Wadsak, W
Jäger, W
Löscher, W
Hacker, M
Zeitlinger, M
Langer, O
Pilot PET Study to Assess the Functional Interplay Between ABCB1 and ABCG2 at the Human Blood–Brain Barrier
title Pilot PET Study to Assess the Functional Interplay Between ABCB1 and ABCG2 at the Human Blood–Brain Barrier
title_full Pilot PET Study to Assess the Functional Interplay Between ABCB1 and ABCG2 at the Human Blood–Brain Barrier
title_fullStr Pilot PET Study to Assess the Functional Interplay Between ABCB1 and ABCG2 at the Human Blood–Brain Barrier
title_full_unstemmed Pilot PET Study to Assess the Functional Interplay Between ABCB1 and ABCG2 at the Human Blood–Brain Barrier
title_short Pilot PET Study to Assess the Functional Interplay Between ABCB1 and ABCG2 at the Human Blood–Brain Barrier
title_sort pilot pet study to assess the functional interplay between abcb1 and abcg2 at the human blood–brain barrier
topic Clinical Trial
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979595/
https://www.ncbi.nlm.nih.gov/pubmed/26940368
http://dx.doi.org/10.1002/cpt.362
work_keys_str_mv AT bauerm pilotpetstudytoassessthefunctionalinterplaybetweenabcb1andabcg2atthehumanbloodbrainbarrier
AT romermannk pilotpetstudytoassessthefunctionalinterplaybetweenabcb1andabcg2atthehumanbloodbrainbarrier
AT karchr pilotpetstudytoassessthefunctionalinterplaybetweenabcb1andabcg2atthehumanbloodbrainbarrier
AT wulkersdorferb pilotpetstudytoassessthefunctionalinterplaybetweenabcb1andabcg2atthehumanbloodbrainbarrier
AT stanekj pilotpetstudytoassessthefunctionalinterplaybetweenabcb1andabcg2atthehumanbloodbrainbarrier
AT philippec pilotpetstudytoassessthefunctionalinterplaybetweenabcb1andabcg2atthehumanbloodbrainbarrier
AT maiersalamona pilotpetstudytoassessthefunctionalinterplaybetweenabcb1andabcg2atthehumanbloodbrainbarrier
AT haslacherh pilotpetstudytoassessthefunctionalinterplaybetweenabcb1andabcg2atthehumanbloodbrainbarrier
AT jungbauerc pilotpetstudytoassessthefunctionalinterplaybetweenabcb1andabcg2atthehumanbloodbrainbarrier
AT wadsakw pilotpetstudytoassessthefunctionalinterplaybetweenabcb1andabcg2atthehumanbloodbrainbarrier
AT jagerw pilotpetstudytoassessthefunctionalinterplaybetweenabcb1andabcg2atthehumanbloodbrainbarrier
AT loscherw pilotpetstudytoassessthefunctionalinterplaybetweenabcb1andabcg2atthehumanbloodbrainbarrier
AT hackerm pilotpetstudytoassessthefunctionalinterplaybetweenabcb1andabcg2atthehumanbloodbrainbarrier
AT zeitlingerm pilotpetstudytoassessthefunctionalinterplaybetweenabcb1andabcg2atthehumanbloodbrainbarrier
AT langero pilotpetstudytoassessthefunctionalinterplaybetweenabcb1andabcg2atthehumanbloodbrainbarrier