Increased sinusoidal export of drug glucuronides is a compensative mechanism in liver cirrhosis of mice
Rationale: Liver cirrhosis is known to affect drug pharmacokinetics, but the functional assessment of the underlying pathophysiological alterations in drug metabolism is difficult.Methods: Cirrhosis in mice was induced by repeated treatment with carbon tetrachloride for 12 months. A cocktail of six...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-11-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1279357/full |
| _version_ | 1797561010406555648 |
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| author | Rebekka Fendt Ahmed Ghallab Ahmed Ghallab Maiju Myllys Ute Hofmann Reham Hassan Reham Hassan Zaynab Hobloss Daniela González Lisa Brackhagen Rosemarie Marchan Karolina Edlund Abdel-Latif Seddek Noha Abdelmageed Lars M. Blank Jan-Frederik Schlender Christian H. Holland Jan G. Hengstler Lars Kuepfer |
| author_facet | Rebekka Fendt Ahmed Ghallab Ahmed Ghallab Maiju Myllys Ute Hofmann Reham Hassan Reham Hassan Zaynab Hobloss Daniela González Lisa Brackhagen Rosemarie Marchan Karolina Edlund Abdel-Latif Seddek Noha Abdelmageed Lars M. Blank Jan-Frederik Schlender Christian H. Holland Jan G. Hengstler Lars Kuepfer |
| author_sort | Rebekka Fendt |
| collection | DOAJ |
| description | Rationale: Liver cirrhosis is known to affect drug pharmacokinetics, but the functional assessment of the underlying pathophysiological alterations in drug metabolism is difficult.Methods: Cirrhosis in mice was induced by repeated treatment with carbon tetrachloride for 12 months. A cocktail of six drugs was administered, and parent compounds as well as phase I and II metabolites were quantified in blood, bile, and urine in a time-dependent manner. Pharmacokinetics were modeled in relation to the altered expression of metabolizing enzymes. In discrepancy with computational predictions, a strong increase of glucuronides in blood was observed in cirrhotic mice compared to vehicle controls.Results: The deviation between experimental findings and computational simulations observed by analyzing different hypotheses could be explained by increased sinusoidal export and corresponded to increased expression of export carriers (Abcc3 and Abcc4). Formation of phase I metabolites and clearance of the parent compounds were surprisingly robust in cirrhosis, although the phase I enzymes critical for the metabolism of the administered drugs in healthy mice, Cyp1a2 and Cyp2c29, were downregulated in cirrhotic livers. RNA-sequencing revealed the upregulation of numerous other phase I metabolizing enzymes which may compensate for the lost CYP isoenzymes. Comparison of genome-wide data of cirrhotic mouse and human liver tissue revealed similar features of expression changes, including increased sinusoidal export and reduced uptake carriers.Conclusion: Liver cirrhosis leads to increased blood concentrations of glucuronides because of increased export from hepatocytes into the sinusoidal blood. Although individual metabolic pathways are massively altered in cirrhosis, the overall clearance of the parent compounds was relatively robust due to compensatory mechanisms. |
| first_indexed | 2024-03-10T18:08:21Z |
| format | Article |
| id | doaj.art-a00c54ea3cb643a68996f363a731a079 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-03-10T18:08:21Z |
| publishDate | 2023-11-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-a00c54ea3cb643a68996f363a731a0792023-11-20T08:20:47ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-11-011410.3389/fphar.2023.12793571279357Increased sinusoidal export of drug glucuronides is a compensative mechanism in liver cirrhosis of miceRebekka Fendt0Ahmed Ghallab1Ahmed Ghallab2Maiju Myllys3Ute Hofmann4Reham Hassan5Reham Hassan6Zaynab Hobloss7Daniela González8Lisa Brackhagen9Rosemarie Marchan10Karolina Edlund11Abdel-Latif Seddek12Noha Abdelmageed13Lars M. Blank14Jan-Frederik Schlender15Christian H. Holland16Jan G. Hengstler17Lars Kuepfer18Institute for Systems Medicine with Focus on Organ Interaction, University Hospital RWTH Aachen, Aachen, GermanyLeibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Dortmund, GermanyDepartment of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, EgyptLeibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Dortmund, GermanyDr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tübingen, Stuttgart, GermanyLeibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Dortmund, GermanyDepartment of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, EgyptLeibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Dortmund, GermanyLeibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Dortmund, GermanyLeibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Dortmund, GermanyLeibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Dortmund, GermanyLeibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Dortmund, GermanyDepartment of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, EgyptDepartment of Pharmacology, Faculty of Veterinary Medicine, Sohag University, Sohag, EgyptInstitute of Applied Microbiology—iAMB, Aachen Biology and Biotechnology—ABBt, RWTH Aachen University, Aachen, GermanyPharmacometrics, Research and Development, Pharmaceuticals, Bayer AG, Leverkusen, GermanyLeibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Dortmund, GermanyLeibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Dortmund, GermanyInstitute for Systems Medicine with Focus on Organ Interaction, University Hospital RWTH Aachen, Aachen, GermanyRationale: Liver cirrhosis is known to affect drug pharmacokinetics, but the functional assessment of the underlying pathophysiological alterations in drug metabolism is difficult.Methods: Cirrhosis in mice was induced by repeated treatment with carbon tetrachloride for 12 months. A cocktail of six drugs was administered, and parent compounds as well as phase I and II metabolites were quantified in blood, bile, and urine in a time-dependent manner. Pharmacokinetics were modeled in relation to the altered expression of metabolizing enzymes. In discrepancy with computational predictions, a strong increase of glucuronides in blood was observed in cirrhotic mice compared to vehicle controls.Results: The deviation between experimental findings and computational simulations observed by analyzing different hypotheses could be explained by increased sinusoidal export and corresponded to increased expression of export carriers (Abcc3 and Abcc4). Formation of phase I metabolites and clearance of the parent compounds were surprisingly robust in cirrhosis, although the phase I enzymes critical for the metabolism of the administered drugs in healthy mice, Cyp1a2 and Cyp2c29, were downregulated in cirrhotic livers. RNA-sequencing revealed the upregulation of numerous other phase I metabolizing enzymes which may compensate for the lost CYP isoenzymes. Comparison of genome-wide data of cirrhotic mouse and human liver tissue revealed similar features of expression changes, including increased sinusoidal export and reduced uptake carriers.Conclusion: Liver cirrhosis leads to increased blood concentrations of glucuronides because of increased export from hepatocytes into the sinusoidal blood. Although individual metabolic pathways are massively altered in cirrhosis, the overall clearance of the parent compounds was relatively robust due to compensatory mechanisms.https://www.frontiersin.org/articles/10.3389/fphar.2023.1279357/fulldrug metabolismliver cirrhosissinusoidal transportglucuronidesdrug cocktailPBPK |
| spellingShingle | Rebekka Fendt Ahmed Ghallab Ahmed Ghallab Maiju Myllys Ute Hofmann Reham Hassan Reham Hassan Zaynab Hobloss Daniela González Lisa Brackhagen Rosemarie Marchan Karolina Edlund Abdel-Latif Seddek Noha Abdelmageed Lars M. Blank Jan-Frederik Schlender Christian H. Holland Jan G. Hengstler Lars Kuepfer Increased sinusoidal export of drug glucuronides is a compensative mechanism in liver cirrhosis of mice Frontiers in Pharmacology drug metabolism liver cirrhosis sinusoidal transport glucuronides drug cocktail PBPK |
| title | Increased sinusoidal export of drug glucuronides is a compensative mechanism in liver cirrhosis of mice |
| title_full | Increased sinusoidal export of drug glucuronides is a compensative mechanism in liver cirrhosis of mice |
| title_fullStr | Increased sinusoidal export of drug glucuronides is a compensative mechanism in liver cirrhosis of mice |
| title_full_unstemmed | Increased sinusoidal export of drug glucuronides is a compensative mechanism in liver cirrhosis of mice |
| title_short | Increased sinusoidal export of drug glucuronides is a compensative mechanism in liver cirrhosis of mice |
| title_sort | increased sinusoidal export of drug glucuronides is a compensative mechanism in liver cirrhosis of mice |
| topic | drug metabolism liver cirrhosis sinusoidal transport glucuronides drug cocktail PBPK |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1279357/full |
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