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Pharmacokinetic Imaging Using (99m)Tc-Mebrofenin to Untangle the Pattern of Hepatocyte Transporter Disruptions Induced by Endotoxemia in Rats

Endotoxemia-induced inflammation may impact the activity of hepatocyte transporters, which control the hepatobiliary elimination of drugs and bile acids. (99m)Tc-mebrofenin is a non-metabolized substrate of transporters expressed at the different poles of hepatocytes. (99m)Tc-mebrofenin imaging was...

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Autores principales: Marie, Solène, Hernández-Lozano, Irene, Le Vée, Marc, Breuil, Louise, Saba, Wadad, Goislard, Maud, Goutal, Sébastien, Truillet, Charles, Langer, Oliver, Fardel, Olivier, Tournier, Nicolas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9028474/
https://www.ncbi.nlm.nih.gov/pubmed/35455390
http://dx.doi.org/10.3390/ph15040392
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author Marie, Solène
Hernández-Lozano, Irene
Le Vée, Marc
Breuil, Louise
Saba, Wadad
Goislard, Maud
Goutal, Sébastien
Truillet, Charles
Langer, Oliver
Fardel, Olivier
Tournier, Nicolas
author_facet Marie, Solène
Hernández-Lozano, Irene
Le Vée, Marc
Breuil, Louise
Saba, Wadad
Goislard, Maud
Goutal, Sébastien
Truillet, Charles
Langer, Oliver
Fardel, Olivier
Tournier, Nicolas
author_sort Marie, Solène
collection PubMed
description Endotoxemia-induced inflammation may impact the activity of hepatocyte transporters, which control the hepatobiliary elimination of drugs and bile acids. (99m)Tc-mebrofenin is a non-metabolized substrate of transporters expressed at the different poles of hepatocytes. (99m)Tc-mebrofenin imaging was performed in rats after the injection of lipopolysaccharide (LPS). Changes in transporter expression were assessed using quantitative polymerase chain reaction of resected liver samples. Moreover, the particular impact of pharmacokinetic drug–drug interactions in the context of endotoxemia was investigated using rifampicin (40 mg/kg), a potent inhibitor of hepatocyte transporters. LPS increased (99m)Tc-mebrofenin exposure in the liver (1.7 ± 0.4-fold). Kinetic modeling revealed that endotoxemia did not impact the blood-to-liver uptake of (99m)Tc-mebrofenin, which is mediated by organic anion-transporting polypeptide (Oatp) transporters. However, liver-to-bile and liver-to-blood efflux rates were dramatically decreased, leading to liver accumulation. The transcriptomic profile of hepatocyte transporters consistently showed a downregulation of multidrug resistance-associated proteins 2 and 3 (Mrp2 and Mrp3), which mediate the canalicular and sinusoidal efflux of (99m)Tc-mebrofenin in hepatocytes, respectively. Rifampicin effectively blocked both the Oatp-mediated influx and the Mrp2/3-related efflux of (99m)Tc-mebrofenin. The additive impact of endotoxemia and rifampicin led to a 3.0 ± 1.3-fold increase in blood exposure compared with healthy non-treated animals. (99m)Tc-mebrofenin imaging is useful to investigate disease-associated change in hepatocyte transporter function.
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spelling pubmed-90284742022-04-23 Pharmacokinetic Imaging Using (99m)Tc-Mebrofenin to Untangle the Pattern of Hepatocyte Transporter Disruptions Induced by Endotoxemia in Rats Marie, Solène Hernández-Lozano, Irene Le Vée, Marc Breuil, Louise Saba, Wadad Goislard, Maud Goutal, Sébastien Truillet, Charles Langer, Oliver Fardel, Olivier Tournier, Nicolas Pharmaceuticals (Basel) Article Endotoxemia-induced inflammation may impact the activity of hepatocyte transporters, which control the hepatobiliary elimination of drugs and bile acids. (99m)Tc-mebrofenin is a non-metabolized substrate of transporters expressed at the different poles of hepatocytes. (99m)Tc-mebrofenin imaging was performed in rats after the injection of lipopolysaccharide (LPS). Changes in transporter expression were assessed using quantitative polymerase chain reaction of resected liver samples. Moreover, the particular impact of pharmacokinetic drug–drug interactions in the context of endotoxemia was investigated using rifampicin (40 mg/kg), a potent inhibitor of hepatocyte transporters. LPS increased (99m)Tc-mebrofenin exposure in the liver (1.7 ± 0.4-fold). Kinetic modeling revealed that endotoxemia did not impact the blood-to-liver uptake of (99m)Tc-mebrofenin, which is mediated by organic anion-transporting polypeptide (Oatp) transporters. However, liver-to-bile and liver-to-blood efflux rates were dramatically decreased, leading to liver accumulation. The transcriptomic profile of hepatocyte transporters consistently showed a downregulation of multidrug resistance-associated proteins 2 and 3 (Mrp2 and Mrp3), which mediate the canalicular and sinusoidal efflux of (99m)Tc-mebrofenin in hepatocytes, respectively. Rifampicin effectively blocked both the Oatp-mediated influx and the Mrp2/3-related efflux of (99m)Tc-mebrofenin. The additive impact of endotoxemia and rifampicin led to a 3.0 ± 1.3-fold increase in blood exposure compared with healthy non-treated animals. (99m)Tc-mebrofenin imaging is useful to investigate disease-associated change in hepatocyte transporter function. MDPI 2022-03-24 /pmc/articles/PMC9028474/ /pubmed/35455390 http://dx.doi.org/10.3390/ph15040392 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Marie, Solène
Hernández-Lozano, Irene
Le Vée, Marc
Breuil, Louise
Saba, Wadad
Goislard, Maud
Goutal, Sébastien
Truillet, Charles
Langer, Oliver
Fardel, Olivier
Tournier, Nicolas
Pharmacokinetic Imaging Using (99m)Tc-Mebrofenin to Untangle the Pattern of Hepatocyte Transporter Disruptions Induced by Endotoxemia in Rats
title Pharmacokinetic Imaging Using (99m)Tc-Mebrofenin to Untangle the Pattern of Hepatocyte Transporter Disruptions Induced by Endotoxemia in Rats
title_full Pharmacokinetic Imaging Using (99m)Tc-Mebrofenin to Untangle the Pattern of Hepatocyte Transporter Disruptions Induced by Endotoxemia in Rats
title_fullStr Pharmacokinetic Imaging Using (99m)Tc-Mebrofenin to Untangle the Pattern of Hepatocyte Transporter Disruptions Induced by Endotoxemia in Rats
title_full_unstemmed Pharmacokinetic Imaging Using (99m)Tc-Mebrofenin to Untangle the Pattern of Hepatocyte Transporter Disruptions Induced by Endotoxemia in Rats
title_short Pharmacokinetic Imaging Using (99m)Tc-Mebrofenin to Untangle the Pattern of Hepatocyte Transporter Disruptions Induced by Endotoxemia in Rats
title_sort pharmacokinetic imaging using (99m)tc-mebrofenin to untangle the pattern of hepatocyte transporter disruptions induced by endotoxemia in rats
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9028474/
https://www.ncbi.nlm.nih.gov/pubmed/35455390
http://dx.doi.org/10.3390/ph15040392
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