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

Irene Hernández-Lozano; Severin Mairinger; Thomas Filip; Michael Sauberer; Thomas Wanek; Johann Stanek; Johannes A Sake; Thomas Pekar; Carsten Ehrhardt; Oliver Langer

doi:10.1016/j.jconrel.2021.12.031

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

J Control Release. 2022 Feb:342:44-52. doi: 10.1016/j.jconrel.2021.12.031. Epub 2021 Dec 28.

Authors

Affiliations

¹ Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
² Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria; Preclinical Molecular Imaging, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria.
³ Preclinical Molecular Imaging, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria; Center for Biomedical Research, Medical University of Vienna, Vienna, Austria.
⁴ Preclinical Molecular Imaging, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria; Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Austria.
⁵ School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
⁶ Biomedical Sciences, University of Applied Sciences Wiener Neustadt, Wiener Neustadt, Austria.
⁷ Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria; Preclinical Molecular Imaging, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria; Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Austria. Electronic address: oliver.langer@meduniwien.ac.at.

PMID: 34971693
DOI: 10.1016/j.jconrel.2021.12.031

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)-[¹¹C]verapamil ([¹¹C]VPM) and [¹¹C]-N-desmethyl-loperamide ([¹¹C]dLOP) administered by intratracheal aerosolization in three rat groups: wild-type, Abcb1a/b^(-/-) and wild-type treated with the P-gp inhibitor tariquidar. Lung exposure (AUC_{lung_right}) to [¹¹C]VPM was 64% and 50% lower (p < 0.05) in tariquidar-treated and in Abcb1a/b^(-/-) rats, respectively, compared to untreated wild-type rats. For [¹¹C]dLOP, AUC_{lung_right} was 59% and 34% lower (p < 0.05) in tariquidar-treated and in Abcb1a/b^(-/-) 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.

Keywords: P-glycoprotein; Positron emission tomography; Pulmonary drug delivery; Pulmonary epithelial barrier.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B / metabolism
ATP Binding Cassette Transporter, Subfamily B, Member 1* / metabolism
Animals
Blood-Brain Barrier* / metabolism
Lung / diagnostic imaging
Lung / metabolism
Positron-Emission Tomography / methods
Rats

Substances

ATP Binding Cassette Transporter, Subfamily B
ATP Binding Cassette Transporter, Subfamily B, Member 1