Predicting drug-induced cholestasis: preclinical models

ABSTRACT

Introduction: In almost 50% of patients with drug-induced liver injury (DILI), the bile flow from the liver to the duodenum is impaired, a condition known as cholestasis. However, this toxic response only appears in a small percentage of the treated patients (idiosyncrasy). Prediction of drug-induced cholestasis (DIC) is challenging and emerges as a safety issue that requires attention by professionals in clinical practice, regulatory authorities, pharmaceutical companies, and research institutions.

Area covered: The current synopsis focuses on the state-of-the-art in preclinical models for cholestatic DILI prediction. These models differ in their goal, complexity, availability, and applicability, and can widely be classified in experimental animals and in vitro models.

Expert opinion: Drugs are a growing cause of cholestasis, but the progress made in explaining mechanisms and differences in susceptibility is not growing at the same rate. We need reliable models able to recapitulate the features of DIC, particularly its idiosyncrasy. The homogeneity and the species-specific differences move animal models away from a fair predictability. However, in vitro human models are improving and getting closer to the real hepatocyte phenotype, and they will likely be the choice in the near future. Progress in this area will not only need reliable predictive models but also mechanistic insights.

KEYWORDS:

• Cholestatic drug
• DILI
• preclinical models
• hepatocyte
• bile acid
• drug transporters
• cell lines
• cholestasis

Article highlights

• The majority of the compounds that cause idiosyncratic DILI in patients gave false negative results in preclinical in vivo models, most probably due to inter-species differences in bile acid metabolism and reduced genetic variability of the experimental animals.

• Some of the limitations of the animal models could be circumvented by increasing the genetic diversity by employing several inbred strains of animals in the same preclinical study.

• The efflux transporter BSEP, expressed on the canalicular membranes of the hepatocytes, is primarily responsible for excretion of bile acids. There are various in vitro assays for evaluating the inhibitory effect of new drugs on BSEP function, but these assays should not be the only ones used to predict drug-induced cholestasis.

• HepaRG and Upcyte hepatocytes hold a great potential for predicting pro-cholestatic drugs due to their functional bile acid metabolism and transport.

• Novel molecular tools such as FRET-based bile acid sensors and fluorescent bile acid analogs could facilitate the real-time quantification of the uptake and efflux of bile acids in vitro.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer declaration of interest

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

The authors acknowledge financial support from the ALIVE Foundation, CIBEREHD, the Instituto de Salud Carlos III (Spanish Ministry of Economy and Competitiveness)‐FEDER (EU) fund (grant number PI17/01089) and Hecatos EU Research Project (European Commission Seventh Framework Programme,  Project ID: HEALTH-F4-2013-602156).