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A3907, a systemic ASBT inhibitor, improves cholestasis in mice by multiorgan activity and shows translational relevance to humans
BACKGROUND AND AIMS: Cholestasis is characterized by intrahepatic accumulation of bile constituents, including bile acids (BAs), which promote liver damage. The apical sodium-dependent BA transporter (ASBT) plays an important role in BA reabsorption and signaling in ileum, bile ducts, and kidneys. O...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Lippincott Williams & Wilkins
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10442107/ https://www.ncbi.nlm.nih.gov/pubmed/36999529 http://dx.doi.org/10.1097/HEP.0000000000000376 |
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author | Caballero-Camino, Francisco J. Rodrigues, Pedro M. Wångsell, Fredrik Agirre-Lizaso, Aloña Olaizola, Paula Izquierdo-Sanchez, Laura Perugorria, Maria J. Bujanda, Luis Angelin, Bo Straniero, Sara Wallebäck, Anna Starke, Ingemar Gillberg, Per-Göran Strängberg, Ellen Bonn, Britta Mattsson, Jan P. Madsen, Martin R. Hansen, Henrik H. Lindström, Erik Åkerblad, Peter Banales, Jesus M. |
author_facet | Caballero-Camino, Francisco J. Rodrigues, Pedro M. Wångsell, Fredrik Agirre-Lizaso, Aloña Olaizola, Paula Izquierdo-Sanchez, Laura Perugorria, Maria J. Bujanda, Luis Angelin, Bo Straniero, Sara Wallebäck, Anna Starke, Ingemar Gillberg, Per-Göran Strängberg, Ellen Bonn, Britta Mattsson, Jan P. Madsen, Martin R. Hansen, Henrik H. Lindström, Erik Åkerblad, Peter Banales, Jesus M. |
author_sort | Caballero-Camino, Francisco J. |
collection | PubMed |
description | BACKGROUND AND AIMS: Cholestasis is characterized by intrahepatic accumulation of bile constituents, including bile acids (BAs), which promote liver damage. The apical sodium-dependent BA transporter (ASBT) plays an important role in BA reabsorption and signaling in ileum, bile ducts, and kidneys. Our aim was to investigate the pharmacokinetics and pharmacological activity of A3907, an oral and systemically available ASBT inhibitor in experimental mouse models of cholestasis. In addition, the tolerability, pharmacokinetics, and pharmacodynamics of A3907 were examined in healthy humans. APPROACH AND RESULTS: A3907 was a potent and selective ASBT inhibitor in vitro. In rodents, orally administered A3907 distributed to the ASBT-expressing organs, that is, ileum, liver, and kidneys, and dose dependently increased fecal BA excretion. A3907 improved biochemical, histological, and molecular markers of liver and bile duct injury in Mdr2 ( −/− ) mice and also had direct protective effects on rat cholangiocytes exposed to cytotoxic BA concentrations in vitro. In bile duct ligated mice, A3907 increased urinary BA elimination, reduced serum BA levels, and prevented body weight loss, while improving markers of liver injury. A3907 was well tolerated and demonstrated target engagement in healthy volunteers. Plasma exposure of A3907 in humans was within the range of systemic concentrations that achieved therapeutic efficacy in mouse. CONCLUSIONS: The systemic ASBT inhibitor A3907 improved experimental cholestatic disease by targeting ASBT function at the intestinal, liver, and kidney levels, resulting in marked clearance of circulating BAs and liver protection. A3907 is well tolerated in humans, supporting further clinical development for the treatment of cholestatic liver diseases. |
format | Online Article Text |
id | pubmed-10442107 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Lippincott Williams & Wilkins |
record_format | MEDLINE/PubMed |
spelling | pubmed-104421072023-08-22 A3907, a systemic ASBT inhibitor, improves cholestasis in mice by multiorgan activity and shows translational relevance to humans Caballero-Camino, Francisco J. Rodrigues, Pedro M. Wångsell, Fredrik Agirre-Lizaso, Aloña Olaizola, Paula Izquierdo-Sanchez, Laura Perugorria, Maria J. Bujanda, Luis Angelin, Bo Straniero, Sara Wallebäck, Anna Starke, Ingemar Gillberg, Per-Göran Strängberg, Ellen Bonn, Britta Mattsson, Jan P. Madsen, Martin R. Hansen, Henrik H. Lindström, Erik Åkerblad, Peter Banales, Jesus M. Hepatology Original Articles: Immune-Mediated Diseases, DILI, and Biliary Tract Disease BACKGROUND AND AIMS: Cholestasis is characterized by intrahepatic accumulation of bile constituents, including bile acids (BAs), which promote liver damage. The apical sodium-dependent BA transporter (ASBT) plays an important role in BA reabsorption and signaling in ileum, bile ducts, and kidneys. Our aim was to investigate the pharmacokinetics and pharmacological activity of A3907, an oral and systemically available ASBT inhibitor in experimental mouse models of cholestasis. In addition, the tolerability, pharmacokinetics, and pharmacodynamics of A3907 were examined in healthy humans. APPROACH AND RESULTS: A3907 was a potent and selective ASBT inhibitor in vitro. In rodents, orally administered A3907 distributed to the ASBT-expressing organs, that is, ileum, liver, and kidneys, and dose dependently increased fecal BA excretion. A3907 improved biochemical, histological, and molecular markers of liver and bile duct injury in Mdr2 ( −/− ) mice and also had direct protective effects on rat cholangiocytes exposed to cytotoxic BA concentrations in vitro. In bile duct ligated mice, A3907 increased urinary BA elimination, reduced serum BA levels, and prevented body weight loss, while improving markers of liver injury. A3907 was well tolerated and demonstrated target engagement in healthy volunteers. Plasma exposure of A3907 in humans was within the range of systemic concentrations that achieved therapeutic efficacy in mouse. CONCLUSIONS: The systemic ASBT inhibitor A3907 improved experimental cholestatic disease by targeting ASBT function at the intestinal, liver, and kidney levels, resulting in marked clearance of circulating BAs and liver protection. A3907 is well tolerated in humans, supporting further clinical development for the treatment of cholestatic liver diseases. Lippincott Williams & Wilkins 2023-09 2023-04-01 /pmc/articles/PMC10442107/ /pubmed/36999529 http://dx.doi.org/10.1097/HEP.0000000000000376 Text en Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/) (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) |
spellingShingle | Original Articles: Immune-Mediated Diseases, DILI, and Biliary Tract Disease Caballero-Camino, Francisco J. Rodrigues, Pedro M. Wångsell, Fredrik Agirre-Lizaso, Aloña Olaizola, Paula Izquierdo-Sanchez, Laura Perugorria, Maria J. Bujanda, Luis Angelin, Bo Straniero, Sara Wallebäck, Anna Starke, Ingemar Gillberg, Per-Göran Strängberg, Ellen Bonn, Britta Mattsson, Jan P. Madsen, Martin R. Hansen, Henrik H. Lindström, Erik Åkerblad, Peter Banales, Jesus M. A3907, a systemic ASBT inhibitor, improves cholestasis in mice by multiorgan activity and shows translational relevance to humans |
title | A3907, a systemic ASBT inhibitor, improves cholestasis in mice by multiorgan activity and shows translational relevance to humans |
title_full | A3907, a systemic ASBT inhibitor, improves cholestasis in mice by multiorgan activity and shows translational relevance to humans |
title_fullStr | A3907, a systemic ASBT inhibitor, improves cholestasis in mice by multiorgan activity and shows translational relevance to humans |
title_full_unstemmed | A3907, a systemic ASBT inhibitor, improves cholestasis in mice by multiorgan activity and shows translational relevance to humans |
title_short | A3907, a systemic ASBT inhibitor, improves cholestasis in mice by multiorgan activity and shows translational relevance to humans |
title_sort | a3907, a systemic asbt inhibitor, improves cholestasis in mice by multiorgan activity and shows translational relevance to humans |
topic | Original Articles: Immune-Mediated Diseases, DILI, and Biliary Tract Disease |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10442107/ https://www.ncbi.nlm.nih.gov/pubmed/36999529 http://dx.doi.org/10.1097/HEP.0000000000000376 |
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