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Quantitative Systems Toxicology Modeling Predicts that Reduced Biliary Efflux Contributes to Tolvaptan Hepatotoxicity.

Author: BeaudoinJames J, BrockWilliam J, BrouwerKim L R, WatkinsPaul B

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, N.I.H., ExtramuralResearch funding provided by the NIH to external research institutions and researchers.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Overview

Patients with autosomal dominant polycystic kidney disease (ADPKD) are more susceptible to tolvaptan-associated hepatotoxicity. The study found that reduced biliary excretion of a major tolvaptan metabolite, DM-4103, led to hepatic bile acid accumulation and increased hepatotoxicity. In vitro studies confirmed that impaired MRP2 function, a biliary efflux transporter, contributed to tolvaptan-associated cytotoxicity. These findings suggest that reduced biliary efflux of tolvaptan and/or DM-4103 may explain increased hepatotoxicity susceptibility in ADPKD patients.
Paper Details　
Original Abstract of the Article :
Patients with autosomal dominant polycystic kidney disease (ADPKD) exhibit enhanced susceptibility to tolvaptan hepatotoxicity relative to other patient populations. In a rodent model of ADPKD, the expression and function of the biliary efflux transporter Mrp2 was reduced, and biliary excretion of a...See full text at original site
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引用元：
https://pubmed.ncbi.nlm.nih.gov/32748396

データ提供：米国国立医学図書館（NLM）

Tolvaptan Hepatotoxicity: Exploring the Role of Biliary Efflux

Tolvaptan, a medication used to treat autosomal dominant polycystic kidney disease (ADPKD), has been linked to hepatotoxicity. This study investigates whether reduced biliary efflux, the process of eliminating substances from the body through bile, contributes to this toxicity. Researchers used a combination of quantitative systems toxicology (QST) modeling and in-vitro experiments to assess the impact of reduced biliary efflux on tolvaptan-associated hepatotoxicity.

Reduced Biliary Efflux: A Potential Driver of Tolvaptan Toxicity

QST simulations revealed that decreased biliary excretion of a major tolvaptan metabolite, DM-4103, led to substantial hepatic accumulation of bile acids, ultimately contributing to hepatotoxicity. In-vitro experiments corroborated these findings, demonstrating that impaired MRP2 function, a transporter involved in biliary efflux, increased the risk of tolvaptan-associated cytotoxicity. This research suggests that reduced biliary efflux could play a significant role in the development of tolvaptan hepatotoxicity.

Navigating the Complexities of Drug Metabolism: A Journey Through the Liver

The study highlights the importance of understanding drug metabolism and its impact on toxicity. Reduced biliary efflux, a key factor in drug elimination, can lead to drug accumulation and adverse effects. This research underscores the need for personalized medicine approaches that consider individual variations in drug metabolism.

Dr.Camel's Conclusion

This study, like a desert explorer uncovering hidden treasures, reveals the complex interplay between drug metabolism and toxicity. The findings emphasize the importance of considering individual variations in drug metabolism and the role of biliary efflux in determining drug safety. This research provides valuable insights for optimizing drug therapy and minimizing the risk of adverse effects.
Date :
  1. Date Completed 2021-05-21
  2. Date Revised 2022-02-02
Further Info :

Pubmed ID

32748396

DOI: Digital Object Identifier

NIHMS1629143

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Article Analysis
・Side Effects of tolvaptan (kidney disease)
SNS
PICO Info
in preparation
Languages

English

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