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PET imaging to assess the impact of P-glycoprotein on pulmonary drug delivery in rats.

Authors :
Hernández-Lozano I
Mairinger S
Filip T
Sauberer M
Wanek T
Stanek J
Sake JA
Pekar T
Ehrhardt C
Langer O
Source :
Journal of controlled release : official journal of the Controlled Release Society [J Control Release] 2022 Feb; Vol. 342, pp. 44-52. Date of Electronic Publication: 2021 Dec 28.
Publication Year :
2022

Abstract

Several drugs approved for inhalation for the treatment of pulmonary diseases are substrates of the adenosine triphosphate-binding cassette (ABC) transporter P-glycoprotein (P-gp). P-gp is expressed in the apical membrane of pulmonary epithelial cells and could play a role in modulating the pulmonary absorption and distribution of inhaled drugs, thereby potentially contributing to variability in therapeutic response and/or systemic side effects. We developed a new in vivo experimental approach to assess the functional impact of P-gp on the pulmonary delivery of inhaled drugs in rats. By using positron emission tomography (PET) imaging, we measured the intrapulmonary pharmacokinetics of the model P-gp substrates (R)-[ <superscript>11</superscript> C]verapamil ([ <superscript>11</superscript> C]VPM) and [ <superscript>11</superscript> C]-N-desmethyl-loperamide ([ <superscript>11</superscript> C]dLOP) administered by intratracheal aerosolization in three rat groups: wild-type, Abcb1a/b <superscript>(-/-)</superscript> and wild-type treated with the P-gp inhibitor tariquidar. Lung exposure (AUC <subscript>lung_right</subscript> ) to [ <superscript>11</superscript> C]VPM was 64% and 50% lower (p < 0.05) in tariquidar-treated and in Abcb1a/b <superscript>(-/-)</superscript> rats, respectively, compared to untreated wild-type rats. For [ <superscript>11</superscript> C]dLOP, AUC <subscript>lung_right</subscript> was 59% and 34% lower (p < 0.05) in tariquidar-treated and in Abcb1a/b <superscript>(-/-)</superscript> rats, respectively. Our results show that P-gp can affect the pulmonary disposition of inhaled P-gp substrates, whereby a decrease in P-gp activity may lead to lower lung exposure and potentially to a decrease in therapeutic efficacy. Our study highlights the potential of PET imaging with intratracheally aerosolized radiotracers to assess the impact of membrane transporters on pulmonary drug delivery, in rodents and potentially also in humans.<br /> (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Details

Language :
English
ISSN :
1873-4995
Volume :
342
Database :
MEDLINE
Journal :
Journal of controlled release : official journal of the Controlled Release Society
Publication Type :
Academic Journal
Accession number :
34971693
Full Text :
https://doi.org/10.1016/j.jconrel.2021.12.031