Increased sinusoidal export of drug glucuronides is a compensative mechanism in liver cirrhosis of mice

Rebekka Fendt; Ahmed Ghallab; Maiju Myllys; Ute Hofmann; 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

doi:10.3389/fphar.2023.1279357

Increased sinusoidal export of drug glucuronides is a compensative mechanism in liver cirrhosis of mice

Front Pharmacol. 2023 Nov 20:14:1279357. doi: 10.3389/fphar.2023.1279357. eCollection 2023.

Authors

Rebekka Fendt^#¹, Ahmed Ghallab^#^{2

3}, Maiju Myllys², Ute Hofmann⁴, Reham Hassan^{2

3}, Zaynab Hobloss², Daniela González², Lisa Brackhagen², Rosemarie Marchan², Karolina Edlund², Abdel-Latif Seddek³, Noha Abdelmageed⁵, Lars M Blank⁶, Jan-Frederik Schlender⁷, Christian H Holland², Jan G Hengstler², Lars Kuepfer¹

Affiliations

¹ Institute for Systems Medicine with Focus on Organ Interaction, University Hospital RWTH Aachen, Aachen, Germany.
² Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Dortmund, Germany.
³ Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt.
⁴ Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tübingen, Stuttgart, Germany.
⁵ Department of Pharmacology, Faculty of Veterinary Medicine, Sohag University, Sohag, Egypt.
⁶ Institute of Applied Microbiology-iAMB, Aachen Biology and Biotechnology-ABBt, RWTH Aachen University, Aachen, Germany.
⁷ Pharmacometrics, Research and Development, Pharmaceuticals, Bayer AG, Leverkusen, Germany.

^# Contributed equally.

Abstract

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.

Keywords: PBPK; drug cocktail; drug metabolism; glucuronides; liver cirrhosis; sinusoidal transport; systems medicine; systems pharmacology.

Grants and funding

The authors declare financial support was received for the research, authorship, and/or publication of this article. RF, LK, and J-FS were funded by the BMBF (Germany) funded project LiSyM (031L0039). LB received funding from the German Research Foundation (DFG)—Project-ID 403224013—SFB 1382. AG was funded by the DFG (Project Ids 517010379 and 457840828) and by the BMBF funded project LiSyM (FKZ 031L0052). UH was funded by the Robert Bosch Stiftung (Stuttgart, Germany) and the Federal Ministry of Education and Research (BMBF, Germany) within the research network LiSyM (031L0037).