Current insights in the complexities underlying drug-induced cholestasis

Abstract

Drug-induced cholestasis (DIC) poses a major challenge to the pharmaceutical industry and regulatory agencies. It causes both drug attrition and post-approval withdrawal of drugs. DIC represents itself as an impaired secretion and flow of bile, leading to the pathological hepatic and/or systemic accumulation of bile acids (BAs) and their conjugate bile salts. Due to the high number of mechanisms underlying DIC, predicting a compound’s cholestatic potential during early stages of drug development remains elusive. A profound understanding of the different molecular mechanisms of DIC is, therefore, of utmost importance. Although many knowledge gaps and caveats still exist, it is generally accepted that alterations of certain hepatobiliary membrane transporters and changes in hepatocellular morphology may cause DIC. Consequently, liver models, which represent most of these mechanisms, are valuable tools to predict human DIC. Some of these models, such as membrane-based in vitro models, are exceptionally well-suited to investigate specific mechanisms (i.e. transporter inhibition) of DIC, while others, such as liver slices, encompass all relevant biological processes and, therefore, offer a better representation of the in vivo situation. In the current review, we highlight the principal molecular mechanisms associated with DIC and offer an overview and critical appraisal of the different liver models that are currently being used to predict the cholestatic potential of drugs.

Keywords:

• Drug-induced cholestasis
• bile acids
• hepatocytes
• in vitro models
• bile acid homeostasis
• drug transporters
• drug-induced liver injury

Acknowledgments

The authors are grateful for the financial support provided by the Research Foundation Flanders (FWO) (grant number 1S69218N). The authors would also like to thank Dr. Roger O. McClellan and the anonymous reviewers for the valuable feedback received, which helped the authors to improve this article.

Declaration of interest

The current employment affiliation of the authors is as shown on the cover page. The authors have no financial or nonfinancial competing interests to declare and have sole responsibility for the writing and content of the review. None of the authors have participated in any legal, regulatory or advocacy activities related to the contents of the paper during the past five years. No potential conflict of interest was reported by the authors.