Different drug metabolism behavior between species in drug-induced hepatotoxicity: limitations and novel resolutions

Abstract

Drug-induced hepatotoxicity (DIH) in preclinical tests will help reduce drug attrition and development costs. However, the concordance between preclinical animal safety data and human clinical hepatotoxicity is <60%. Species specificity is an important reason. The main limitation caused by species specificity in DIH research is different mechanisms of drug metabolism. Therefore, in vitro models containing human-derived hepatocytes are needed in DIH research. Liver components, including non-parenchymal cells (NPCs), extracellular matrix (ECM) and continuously perfused environment, are essential for maintenance of hepatocyte metabolism. 3D ECM that contains human-derived hepatocytes and NPCs in a continuously perfused environment can be used to investigate drug metabolism in DIH research. In this review article, we summarize the different metabolic activities caused by species specificity in DIH research and describe current novel models, including 3D co-culture in vitro models, to circumvent differences in metabolic activity.

Keywords:

• 3D co-culture
• drug-induced hepatotoxicity
• drug metabolism
• species specificity

Declaration of Interest

The authors report no conflicts of interest.

Additional information

Funding

This article was supported by (1) National Key R&D Program of China (No. 2017YFA0103000); (2) Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support (No. ZYLX201806); (3) “Beijing Muncipal Administration of Hospitals” Ascent Plan (No. DFL20151601); (4) National Science and Technology Key Project on “Major Infectious Diseases such as HIV/AIDS, Viral Hepatitis Preventon and Treatment” (No. 2012ZX10002004-006, 2017ZX10203201-005, 2017ZX10201201-001-001, 2017ZX10201201-002-002, 2017ZX10202203-006-001, 2017ZX10302201-004-002).