Utility of Three-Dimensional Cultures of Primary Human Hepatocytes (Spheroids) as Pharmacokinetic Models

Abstract

This paper reviews the usefulness, current status, and potential of primary human hepatocytes (PHHs) in three-dimensional (3D) cultures, also known as spheroids, in the field of pharmacokinetics (PK). Predicting PK and toxicity means pharmaceutical research can be conducted more efficiently. Various in vitro test systems using human hepatocytes have been proposed as tools to detect hepatic toxicity at an early stage in the drug development process. However, such evaluation requires long-term, low-level exposure to the test compound, and conventional screening systems such as PHHs in planar (2D) culture, in which the cells can only survive for a few days, are unsuitable for this purpose. In contrast, spheroids consisting of PHH are reported to retain the functional characteristics of human liver for at least 35 days. Here, we introduce a fundamental PK and toxicity assessment model of PHH spheroids and describe their applications for assessing species-specific metabolism, enzyme induction, and toxicity, focusing on our own work in these areas. The studies outlined in this paper may provide important information for pharmaceutical companies to reduce termination of development of drug candidates.

Human Three-Dimensional Hepatic Models: Cell Type Variety and Corresponding Applications

“…Scaffold-based techniques utilize natural or synthetic external cell anchoring systems that mimic the ECM to facilitate the formation of cell-cell contacts and tissue organization. Common scaffoldbased 3D culture paradigms include micropatterned co-culture, microcarrier bead configuration, matrix-embedded, hollow fiber bioreactors, and microfluidics systems (Underhill and Khetani, 2018;Lauschke et al, 2019;Mizoi et al, 2020). Furthermore, 3D bioprinting has been applied as a precise layering method to create scaffolds with a tightly controlled architecture and posit cells or spheroids as building blocks in a specified spatial arrangement necessary for tissue formation (Derakhshanfar et al, 2018;Ma et al, 2018).…”

Evaluation of the Safety and Toxicity of the Original Copper Nanocomposite Based on Poly-N-vinylimidazole

“…The study of the ALT and AST activity has recently been used, not only in clinical practice to diagnose diseases associated with impaired liver function, but also to research the toxicity of various drugs to 2D and 3D hepatocyte cultures [ 65 , 66 , 67 , 68 ]. Based on this, in our investigation, the analysis of the AST and ALT activity in the culture medium was used to determine the degree of copper-containing compound toxicity in relation to the primary culture of hepatocytes.…”

3D human liver spheroids for translational pharmacology and toxicology

“…Importantly, however, the functional lifespan of these cultures is very short (<24 hours for 2D cultures and cell suspensions), which limits the utility of these models for slowly metabolized compounds. 3D models, such as spheroids, have the advantage that they can be used for long‐term studies, thus allowing the evaluation of metabolite formation and pharmacokinetic parameters from low clearance drugs 67 . Intrinsic clearance (CL int ) values of the low clearance compounds tested successfully predicted in vivo CL int within 3‐fold 68,69 .…”