Requirements for human iPS cell-derived hepatocytes as an alternative to primary human hepatocytes for assessing absorption, distribution, metabolism, excretion and toxicity of pharmaceuticals

Araki, Tetsuro; Iwazaki, Norihiko; Ishiguro, Naoki; Sakamoto, Atsushi; Nagata, Kenichi; Ohbuchi, Masato; Moriguchi, Hiroyuki; Motoi, Makiko; Shinkyo, Raku; Homma, Toshiki; Sakamoto, Sakae; Iwase, Yumiko; Ise, Ryota; Nakanishi, Yasuharu; Uto, Masahiro; Inoue, Tomoaki

doi:10.2131/fts.3.89

Cited by 4 publications

(1 citation statement)

References 33 publications

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“…Regardless, the current data suggest that our CVM chamber-based vitrigel culture method enhances the metabolic activities of all CYP isoforms examined. For the target values in this method, the most frequently observed value ranges (MFRs) of the activities of major drug metabolizing enzymes (Araki et al, 2016) were approximate references. Although the activities of CYP2C9 and CYP2D6 cannot be referenced because these substrates tested were different, the activity of CYP1A2 in vitrigel culture was approximately half of the value of MFR, and the activities of CYP2C19 and CYP3A were higher.…”

Section: Discussionmentioning

confidence: 99%

A long-term culture system based on a collagen vitrigel membrane chamber that supports liver-specific functions of hepatocytes isolated from mice with humanized livers

et al. 2018

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During drug discovery, in vitro models are used to predict the in vivo pharmacokinetic and toxicological properties of drug candidates in humans. However, the conventional method of culturing human hepatocytes as monolayers does not necessarily replicate biologic reactions and does not support liver-specific functions, such as cytochrome P450 (CYP) activities, for prolonged periods. To remedy these problems and thus increase and prolong hepatic functions, we developed a culture system comprising a collagen vitrigel membrane (CVM) chamber and PXB-cells®, fresh hepatocytes isolated from liver-humanized chimeric mice (PXB-mice®). To quantitatively assess our new system, we evaluated the activities of 5 major CYP isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A), albumin secretion, and urea synthesis. First, between Days 14 and 21, the activities of all CYP isoforms tested in vitrigel culture were equal to or higher than in conventional monolayer culture system. Second, the activities of CYP3A, CYP2C9, and CYP2C19 during Days 10 through 17 were higher in vitrigel culture than in suspended PXB-cells prepared on Day 0 (suspension assay). Third, albumin secretion and urea synthesis were higher in vitrigel culture than in conventional monolayer culture. Fourth, the vitrigel-cultured PXB-cells showed the characteristic morphology of parenchymal hepatocytes and were almost all alive in monolayer. These results indicate that our vitrigel culture method is superior to the conventional monolayer method in terms of diverse liver-specific functions, including CYP activity. Our findings suggest that the vitrigel culture method could be a powerful in vitro tool for predicting the pharmacokinetic and toxicological properties of drug candidates in humans.

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Section: Discussionmentioning

confidence: 99%

A long-term culture system based on a collagen vitrigel membrane chamber that supports liver-specific functions of hepatocytes isolated from mice with humanized livers

et al. 2018

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Engineering considerations of iPSC-based personalized medicine

et al. 2023

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Personalized medicine aims to provide tailored medical treatment that considers the clinical, genetic, and environmental characteristics of patients. iPSCs have attracted considerable attention in the field of personalized medicine; however, the inherent limitations of iPSCs prevent their widespread use in clinical applications. That is, it would be important to develop notable engineering strategies to overcome the current limitations of iPSCs. Such engineering approaches could lead to significant advances in iPSC-based personalized therapy by offering innovative solutions to existing challenges, from iPSC preparation to clinical applications. In this review, we summarize how engineering strategies have been used to advance iPSC-based personalized medicine by categorizing the development process into three distinctive steps: 1) the production of therapeutic iPSCs; 2) engineering of therapeutic iPSCs; and 3) clinical applications of engineered iPSCs. Specifically, we focus on engineering strategies and their implications for each step in the development of iPSC-based personalized medicine.

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Utilization of iPSC Technologies for Drug-Induced Risk and Drug Efficacy Evaluation During Drug Development

Miyamoto

2020

CPB

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Requirements for human iPS cell-derived hepatocytes as an alternative to primary human hepatocytes for assessing absorption, distribution, metabolism, excretion and toxicity of pharmaceuticals

Cited by 4 publications

References 33 publications

A long-term culture system based on a collagen vitrigel membrane chamber that supports liver-specific functions of hepatocytes isolated from mice with humanized livers

A long-term culture system based on a collagen vitrigel membrane chamber that supports liver-specific functions of hepatocytes isolated from mice with humanized livers

Engineering considerations of iPSC-based personalized medicine

Utilization of iPSC Technologies for Drug-Induced Risk and Drug Efficacy Evaluation During Drug Development

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