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Article

Daily Intraperitoneal Administration of Rosiglitazone Does Not Improve Lung Function or Alveolarization in Preterm Rabbits Exposed to Hyperoxia

1
Department of Preclinical Pharmacology, R&D, Chiesi Farmaceutici S.p.A., 43122 Parma, Italy
2
Department of Development and Regeneration, Cluster Woman and Child, KU Leuven, 3000 Leuven, Belgium
3
Scientific Consultancy, 48640 Berango, Spain
4
Department of Veterinary Science, University of Parma, 43121 Parma, Italy
5
Department of Pharmacokinetic, Biochemistry & Metabolism, R&D, Chiesi Farmaceutici S.p.A., 43122 Parma, Italy
6
Department of Analytic and Early Formulations, R&D, Chiesi Farmaceutici S.p.A., 43122 Parma, Italy
7
Department of Chemistry Research & Drug Design, R&D, Chiesi Farmaceutici S.p.A., 43122 Parma, Italy
8
Portfolio Management R & D, Chiesi Farmaceutici S.p.A., 43122 Parma, Italy
9
Department of Paediatrics, University Hospital Leuven, 3000 Leuven, Belgium
10
Leuven Child and Youth Institute, KU Leuven, 3000 Leuven, Belgium
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editors: Kyeong-Ryoon Lee and Yoon-Jee Chae
Pharmaceutics 2022, 14(7), 1507; https://doi.org/10.3390/pharmaceutics14071507
Received: 13 June 2022 / Revised: 11 July 2022 / Accepted: 13 July 2022 / Published: 20 July 2022
(This article belongs to the Special Issue Advances in Pharmacokinetics, Pharmacodynamics and Drug Interactions)
Thiazolidinediones (TZDs) are potent PPARγ agonists that have been shown to attenuate alveolar simplification after prolonged hyperoxia in term rodent models of bronchopulmonary dysplasia. However, the pulmonary outcomes of postnatal TZDs have not been investigated in preterm animal models. Here, we first investigated the PPARγ selectivity, epithelial permeability, and lung tissue binding of three types of TZDs in vitro (rosiglitazone (RGZ), pioglitazone, and DRF-2546), followed by an in vivo study in preterm rabbits exposed to hyperoxia (95% oxygen) to investigate the pharmacokinetics and the pulmonary outcomes of daily RGZ administration. In addition, blood lipids and a comparative lung proteomics analysis were also performed on Day 7. All TZDs showed high epithelial permeability through Caco-2 monolayers and high plasma and lung tissue binding; however, RGZ showed the highest affinity for PPARγ. The pharmacokinetic profiling of RGZ (1 mg/kg) revealed an equivalent biodistribution after either intratracheal or intraperitoneal administration, with detectable levels in lungs and plasma after 24 h. However, daily RGZ doses of 1 mg/kg did not improve lung function in preterm rabbits exposed to hyperoxia, and daily 10 mg/kg doses were even associated with a significant lung function worsening, which could be partially explained by the upregulation of lung inflammation and lipid metabolism pathways revealed by the proteomic analysis. Notably, daily postnatal RGZ produced an aberrant modulation of serum lipids, particularly in rabbit pups treated with the 10 mg/kg dose. In conclusion, daily postnatal RGZ did not improve lung function and caused dyslipidemia in preterm rabbits exposed to hyperoxia. View Full-Text
Keywords: thiazolidinediones; rosiglitazone; pioglitazone; preterm rabbits; bronchopulmonary dysplasia; hyperoxia; dyslipidemia; lung proteomics thiazolidinediones; rosiglitazone; pioglitazone; preterm rabbits; bronchopulmonary dysplasia; hyperoxia; dyslipidemia; lung proteomics
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MDPI and ACS Style

Aquila, G.; Regin, Y.; Murgia, X.; Salomone, F.; Casiraghi, C.; Catozzi, C.; Scalera, E.; Storti, M.; Stretti, F.; Aquino, G.; Cavatorta, G.; Volta, R.; Di Pasquale, C.; Amato, C.; Bignami, F.; Amidani, D.; Pioselli, B.; Sgarbi, E.; Ronchi, P.; Mazzola, G.; Valenzuela, I.; Toelen, J. Daily Intraperitoneal Administration of Rosiglitazone Does Not Improve Lung Function or Alveolarization in Preterm Rabbits Exposed to Hyperoxia. Pharmaceutics 2022, 14, 1507. https://doi.org/10.3390/pharmaceutics14071507

AMA Style

Aquila G, Regin Y, Murgia X, Salomone F, Casiraghi C, Catozzi C, Scalera E, Storti M, Stretti F, Aquino G, Cavatorta G, Volta R, Di Pasquale C, Amato C, Bignami F, Amidani D, Pioselli B, Sgarbi E, Ronchi P, Mazzola G, Valenzuela I, Toelen J. Daily Intraperitoneal Administration of Rosiglitazone Does Not Improve Lung Function or Alveolarization in Preterm Rabbits Exposed to Hyperoxia. Pharmaceutics. 2022; 14(7):1507. https://doi.org/10.3390/pharmaceutics14071507

Chicago/Turabian Style

Aquila, Giorgio, Yannick Regin, Xabier Murgia, Fabrizio Salomone, Costanza Casiraghi, Chiara Catozzi, Enrica Scalera, Matteo Storti, Francesca Stretti, Giancarlo Aquino, Giorgia Cavatorta, Roberta Volta, Carmelina Di Pasquale, Caterina Amato, Fabio Bignami, Davide Amidani, Barbara Pioselli, Elisa Sgarbi, Paolo Ronchi, Giuseppe Mazzola, Ignacio Valenzuela, and Jaan Toelen. 2022. "Daily Intraperitoneal Administration of Rosiglitazone Does Not Improve Lung Function or Alveolarization in Preterm Rabbits Exposed to Hyperoxia" Pharmaceutics 14, no. 7: 1507. https://doi.org/10.3390/pharmaceutics14071507

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