Human liver cell-based assays for the prediction of hepatic bile acid efflux transporter inhibition by drugs.

Introduction: Drug-mediated inhibition of bile salt efflux transporters may cause liver injury. In vitro prediction of drug effects toward canalicular and/or sinusoidal efflux of bile salts from human hepatocytes is therefore a major issue, which can be addressed using liver cell-based assays.

Area covered: This review, based on a thorough literature search in the scientific databases PubMed and Web of Science, provides key information about hepatic transporters implicated in bile salt efflux, the human liver cell models available for investigating functional inhibition of bile salt efflux, the different methodologies used for this purpose, and the modes of expression of the results. Applications of the assays to drugs are summarized, with special emphasis to the performance values of some assays for predicting hepatotoxicity/cholestatic effects of drugs.

Expert opinion: Human liver cell-based assays for evaluating drug-mediated inhibition of bile acid efflux transporters face various limitations, such as the lack of method standardization and validation, the present poor adaptability to high throughput approaches, and some pitfalls with respect to interpretation of bile acid biliary excretion indexes. Hepatotoxicity of drugs is additionally likely multifactorial, highlighting that inhibition of hepatic bile salt efflux by drugs provides important, but not full, information about potential drug hepatotoxicity.