Sandwich-cultured hepatocytes: an in vitro model to evaluate hepatobiliary transporter-based drug interactions and hepatotoxicity

Abstract

Sandwich-cultured hepatocytes (SCH) are a powerful in vitro tool that can be utilized to study hepatobiliary drug transport, species differences in drug transport, transport protein regulation, drug-drug interactions, and hepatotoxicity. This review provides an up-to-date summary of the SCH model, including a brief history of, and introduction to, the use of SCH, as well as methodology to evaluate hepatobiliary drug disposition. A summary of the literature that has utilized this model to examine the interplay between drug-metabolizing enzymes and transport proteins, drug-drug interactions at the transport level, and hepatotoxicity as a result of altered hepatic transport also is provided.

Keywords:

• Sandwich-cultured hepatocytes
• hepatotoxicity
• drug-induced liver injury
• drug-drug interactions
• hepatocellularity
• BEI
• in vitro biliary clearance

Acknowledgements

The authors would like to thank the following individuals: Dr. Xianbin Tian, Ph.D., for providing the fluorescent images of CDF accumulation in wild-type and Abcc2^–/– mouse SCH; Dr. Wei Yue, Ph.D., Tracy Marion, and Katie Paul for providing immunoblots of transport proteins in rat and human SCH; Drs. Peijin Zhang, Ph.D., and Yong Hae Han, Ph.D., for providing immunoblots of modulator effects on Mrp2 and Mrp3, respectively; Dr. Jin Lee, Ph.D., for calculation of the hepatocyte volume in SCH; and Dr. Kenneth Brouwer, Ph.D., for insightful suggestions during the preparation and review of the manuscript for this article.

Declaration of interest

KLRB is a cofounder and chair of the Scientific Advisory Board for Qualyst, Inc., which has exclusively licensed the sandwich-cultured hepatocyte technology for the quantification of biliary excretion (B-CLEAR^®). This research was supported by a grant from the National Institutes of Health (R01 GM41935; Bethesda, Maryland, USA). BS is supported by an Eli Lilly and Company predoctoral fellowship. NDP is supported by the UNC Royster Society of Fellows.