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.
Highlights
This review addresses in vitro evaluation of pharmacokinetics (PK) and associated toxicity, a crucial step in pharmaceutical research
Once the cell line was removed from these results, we found just 15 papers focusing on pharmacokinetic and toxicity studies using primary human hepatocytes (PHHs)
We introduce related evaluation methods using hepatocytes isolated from liver-humanized mice, hepatocytes differentiated from liver progenitor cells, and hepatocytes derived from human induced pluripotent stem cells, which may have similar capabilities to PHHs
Summary
This review addresses in vitro evaluation of pharmacokinetics (PK) and associated toxicity, a crucial step in pharmaceutical research. Cells in 2D culture have essentially unlimited access to medium components such as oxygen, nutrients, metabolites, and signaling molecules, in marked contrast to the in vivo situation [28] To overcome these drawbacks, 3D-cultured hepatocyte systems, which can maintain functions specific to the human liver for a long period of time, have been developed [29]. Once the cell line was removed from these results, we found just 15 papers focusing on pharmacokinetic and toxicity studies using PHHs. we review the current status of applications of spheroid cultures of PHHs to PK (see Table 2), including our own studies using PHH spheroids to assess drug metabolism, enzyme induction, and associated toxicity.
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