Pharmacokinetic Imaging Using <sup>99m</sup>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. <sup>99m</sup>Tc-mebrofenin is a non-metabolized substrate of transporters expressed at the different poles of hepatocytes. <sup>...
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MDPI AG
2022-03-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/15/4/392 |
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| author | Solène Marie Irene Hernández-Lozano Marc Le Vée Louise Breuil Wadad Saba Maud Goislard Sébastien Goutal Charles Truillet Oliver Langer Olivier Fardel Nicolas Tournier |
| author_facet | Solène Marie Irene Hernández-Lozano Marc Le Vée Louise Breuil Wadad Saba Maud Goislard Sébastien Goutal Charles Truillet Oliver Langer Olivier Fardel Nicolas Tournier |
| author_sort | Solène Marie |
| collection | DOAJ |
| description | Endotoxemia-induced inflammation may impact the activity of hepatocyte transporters, which control the hepatobiliary elimination of drugs and bile acids. <sup>99m</sup>Tc-mebrofenin is a non-metabolized substrate of transporters expressed at the different poles of hepatocytes. <sup>99m</sup>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 <sup>99m</sup>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 <sup>99m</sup>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 <sup>99m</sup>Tc-mebrofenin in hepatocytes, respectively. Rifampicin effectively blocked both the Oatp-mediated influx and the Mrp2/3-related efflux of <sup>99m</sup>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. <sup>99m</sup>Tc-mebrofenin imaging is useful to investigate disease-associated change in hepatocyte transporter function. |
| first_indexed | 2024-03-09T10:30:53Z |
| format | Article |
| id | doaj.art-27ee7558c859412bb9672fe2db8e091a |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T10:30:53Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-27ee7558c859412bb9672fe2db8e091a2023-12-01T21:17:58ZengMDPI AGPharmaceuticals1424-82472022-03-0115439210.3390/ph15040392Pharmacokinetic Imaging Using <sup>99m</sup>Tc-Mebrofenin to Untangle the Pattern of Hepatocyte Transporter Disruptions Induced by Endotoxemia in RatsSolène Marie0Irene Hernández-Lozano1Marc Le Vée2Louise Breuil3Wadad Saba4Maud Goislard5Sébastien Goutal6Charles Truillet7Oliver Langer8Olivier Fardel9Nicolas Tournier10Université Paris-Saclay, CEA, CNRS, Inserm, Laboratoire d’Imagerie Biomédicale Multimodale, BIOMAPS, Service Hospitalier Frédéric Joliot, 4 Place du Général Leclerc, 91401 Orsay, FranceDepartment of Clinical Pharmacology, Medical University of Vienna, 1090 Vienna, AustriaUniv. Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail)-UMR_S 1085, 35043 Rennes, FranceUniversité Paris-Saclay, CEA, CNRS, Inserm, Laboratoire d’Imagerie Biomédicale Multimodale, BIOMAPS, Service Hospitalier Frédéric Joliot, 4 Place du Général Leclerc, 91401 Orsay, FranceUniversité Paris-Saclay, CEA, CNRS, Inserm, Laboratoire d’Imagerie Biomédicale Multimodale, BIOMAPS, Service Hospitalier Frédéric Joliot, 4 Place du Général Leclerc, 91401 Orsay, FranceUniversité Paris-Saclay, CEA, CNRS, Inserm, Laboratoire d’Imagerie Biomédicale Multimodale, BIOMAPS, Service Hospitalier Frédéric Joliot, 4 Place du Général Leclerc, 91401 Orsay, FranceUniversité Paris-Saclay, CEA, CNRS, Inserm, Laboratoire d’Imagerie Biomédicale Multimodale, BIOMAPS, Service Hospitalier Frédéric Joliot, 4 Place du Général Leclerc, 91401 Orsay, FranceUniversité Paris-Saclay, CEA, CNRS, Inserm, Laboratoire d’Imagerie Biomédicale Multimodale, BIOMAPS, Service Hospitalier Frédéric Joliot, 4 Place du Général Leclerc, 91401 Orsay, FranceDepartment of Clinical Pharmacology, Medical University of Vienna, 1090 Vienna, AustriaUniv. Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail)-UMR_S 1085, 35043 Rennes, FranceUniversité Paris-Saclay, CEA, CNRS, Inserm, Laboratoire d’Imagerie Biomédicale Multimodale, BIOMAPS, Service Hospitalier Frédéric Joliot, 4 Place du Général Leclerc, 91401 Orsay, FranceEndotoxemia-induced inflammation may impact the activity of hepatocyte transporters, which control the hepatobiliary elimination of drugs and bile acids. <sup>99m</sup>Tc-mebrofenin is a non-metabolized substrate of transporters expressed at the different poles of hepatocytes. <sup>99m</sup>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 <sup>99m</sup>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 <sup>99m</sup>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 <sup>99m</sup>Tc-mebrofenin in hepatocytes, respectively. Rifampicin effectively blocked both the Oatp-mediated influx and the Mrp2/3-related efflux of <sup>99m</sup>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. <sup>99m</sup>Tc-mebrofenin imaging is useful to investigate disease-associated change in hepatocyte transporter function.https://www.mdpi.com/1424-8247/15/4/392ABC-transporterdrug-induced liver injuryhepatotoxicityorganic anion-transporting polypeptidepharmacokineticsliver function |
| spellingShingle | Solène Marie Irene Hernández-Lozano Marc Le Vée Louise Breuil Wadad Saba Maud Goislard Sébastien Goutal Charles Truillet Oliver Langer Olivier Fardel Nicolas Tournier Pharmacokinetic Imaging Using <sup>99m</sup>Tc-Mebrofenin to Untangle the Pattern of Hepatocyte Transporter Disruptions Induced by Endotoxemia in Rats Pharmaceuticals ABC-transporter drug-induced liver injury hepatotoxicity organic anion-transporting polypeptide pharmacokinetics liver function |
| title | Pharmacokinetic Imaging Using <sup>99m</sup>Tc-Mebrofenin to Untangle the Pattern of Hepatocyte Transporter Disruptions Induced by Endotoxemia in Rats |
| title_full | Pharmacokinetic Imaging Using <sup>99m</sup>Tc-Mebrofenin to Untangle the Pattern of Hepatocyte Transporter Disruptions Induced by Endotoxemia in Rats |
| title_fullStr | Pharmacokinetic Imaging Using <sup>99m</sup>Tc-Mebrofenin to Untangle the Pattern of Hepatocyte Transporter Disruptions Induced by Endotoxemia in Rats |
| title_full_unstemmed | Pharmacokinetic Imaging Using <sup>99m</sup>Tc-Mebrofenin to Untangle the Pattern of Hepatocyte Transporter Disruptions Induced by Endotoxemia in Rats |
| title_short | Pharmacokinetic Imaging Using <sup>99m</sup>Tc-Mebrofenin to Untangle the Pattern of Hepatocyte Transporter Disruptions Induced by Endotoxemia in Rats |
| title_sort | pharmacokinetic imaging using sup 99m sup tc mebrofenin to untangle the pattern of hepatocyte transporter disruptions induced by endotoxemia in rats |
| topic | ABC-transporter drug-induced liver injury hepatotoxicity organic anion-transporting polypeptide pharmacokinetics liver function |
| url | https://www.mdpi.com/1424-8247/15/4/392 |
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