Recent Progress in Hepatocyte Culture Models and Their Application to the Assessment of Drug Metabolism, Transport, and Toxicity in Drug Discovery: The Value of Tissue Engineering for the Successful Development of a Microphysiological System

Tetsuka, Kazuhiro; Ohbuchi, Masato; Tabata, Kenji

doi:10.1016/j.xphs.2017.05.010

Cited by 39 publications

(24 citation statements)

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“…Human induced pluripotent stem (iPS) cell-derived hepatocytes may also serve as an alternative to h-PRM-HEP [6]; however, fewer metabolic reactions occur in iPS cells than in h-PRM-HEP [7]. Additionally, new methodologies for cell culture, such as three-dimensional culture methods, have been developed [8]. …”

Section: Introductionmentioning

confidence: 99%

Use of hepatocytes isolated from a liver-humanized mouse for studies on the metabolism of drugs: application to the metabolism of fentanyl and acetylfentanyl

et al. 2018

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PurposeThe usefulness of hepatocytes isolated from a liver-humanized mouse (PXB-cells) as a model in vitro system for the prediction of the in vivo metabolism of new drugs of abuse was evaluated.MethodsFor the drug metabolism study, fentanyl, a powerful synthetic opioid, and acetylfentanyl, an N-acetyl analog of fentanyl, were selected as model drugs. PXB-cells were cultured with the drug for 24–48 h and then the media were collected and analyzed by liquid chromatography/mass spectrometry after deproteinization with acetonitrile.ResultsThe main metabolite formed from fentanyl by PXB-cells was the desphenethylated metabolite (nor-fentanyl), and the other major metabolites formed were 4′-hydroxy-fentanyl, β-hydroxy-fentanyl and (ω-1)-hydroxy-fentanyl. ω-Hydroxy-fentanyl and 4′-hydroxy-3′-methoxy-fentanyl were the minor metabolites. Similar results were obtained for acetylfentanyl. The metabolite profile of fentanyl in PXB-cells was consistent with the in vivo metabolite profile of fentanyl reported previously. Most of the 4′-hydroxy- and 4′-hydroxy-3′-methoxy-metabolites of fentanyl and acetylfentanyl were conjugated in PXB-cells, indicating that PXB-cells had high conjugation enzyme activities. From experiments using human liver microsomes and anti-CYP antibodies, it was revealed that CYP3A4 was involved in the production of nor-fentanyl, β-hydroxy-fentanyl and (ω-1)-hydroxy-fentanyl, while CYP2D6 was partially involved in the production of 4′-hydroxy-fentanyl.ConclusionsOur results indicated that PXB-cells have high activities of phase I and phase II drug-metabolizing-enzymes, can be stably supplied, and are easy to use; thus, PXB-cells are highly useful for the prediction of the in vivo metabolism of drugs of abuse.

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Section: Introductionmentioning

confidence: 99%

Use of hepatocytes isolated from a liver-humanized mouse for studies on the metabolism of drugs: application to the metabolism of fentanyl and acetylfentanyl

et al. 2018

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“…1) h-PRM-HEP are regarded as one of the best tools for the investigation of the metabolism of drugs; however, there are problems with their use, including maintaining a stable supply of cells of a consistent quality and occasional significant drops in cell viability resulting from the fragility of the cells.…”

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confidence: 99%

Metabolism of Fentanyl and Acetylfentanyl in Human-Induced Pluripotent Stem Cell-Derived Hepatocytes

Kanamori

Iwata

Segawa

et al. 2018

Biological & Pharmaceutical Bulletin

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To evaluate the capability of human-induced pluripotent stem cell-derived hepatocytes (h-iPS-HEP) in drug metabolism, the profiles of the metabolites of fentanyl, a powerful synthetic opioid, and acetylfentanyl, an N-acetyl analog of fentanyl, in the cells were determined and analyzed. Commercially available h-iPS-HEP were incubated with fentanyl or acetylfentanyl for 24 or 48 h. After enzymatic hydrolysis, the medium was deproteinized with acetonitrile, then analyzed by LC/MS. Desphenethylated metabolites and some hydroxylated metabolites, including 4′-hydroxy-fentanyl and β-hydroxy-fentanyl, were detected as metabolites of fentanyl and acetylfentanyl in the medium. The main metabolite of fentanyl with h-iPS-HEP was the desphenethylated metabolite, which was in agreement with in vivo results. These results suggest that h-iPS-HEP may be useful as a tool for investigating drug metabolism.Key words induced pluripotent stem cell; hepatocyte; fentanyl; metabolism Human primary hepatocytes (h-PRM-HEP) are widely used for drug metabolism studies because they are highly active in phase I and phase II drug metabolism.1) h-PRM-HEP are regarded as one of the best tools for the investigation of the metabolism of drugs; however, there are problems with their use, including maintaining a stable supply of cells of a consistent quality and occasional significant drops in cell viability resulting from the fragility of the cells. 2)Induced pluripotent stem (iPS) cells, first developed in 2006, can differentiate into many different types of cells, including neurons, cardiomyocytes, and hepatocytes.3) Human iPS cell-derived hepatocytes (h-iPS-HEP) reportedly have catalytic activity from various CYP enzymes, in addition to liver-specific functions, such as albumin secretion and ammonia metabolism.4) Furthermore, h-iPS-HEP are robust and can be supplied stably, making these cells a potentially useful tool for drug metabolism studies.In this study, we investigated the ability of h-iPS-HEP to metabolize drugs using fentanyl and acetylfentanyl (Fig. 1) as model drugs. Fentanyl is a powerful synthetic opioid, which is used as an analgesic in patients with cancer. 5) Acetylfentanyl is an N-acetyl analog of fentanyl, which is used as a substitute for recreational opioid drugs, such as heroin.6) Fentanyl is known to be metabolized by desphenethylation, 4′-hydroxylation, and hydroxylation of the N-propionyl group. 7) Acetylfentanyl is metabolized in a similar manner to fentanyl. 8) We evaluated how accurately the in vivo patterns of fentanyl and acetylfentanyl metabolism can be reproduced using h-iPS-HEP. MATERIALS AND METHODSMaterials Authentic standards of fentanyl, acetylfentanyl, and their metabolites were synthesized in our laboratory. cis-3-Methylfentanyl was synthesized in our laboratory by the method reported previously. 9) β-Glucuronidase/aryl sulfatase (from Helix pomatia; β-glucuronidase, 32 units/mL; aryl sulfatase, 102 units/mL) was purchased from Merck (Darmstadt,

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“…Uncovering molecular communications between a bone tissue model and other organs or tissues, such as muscle (Brotto & Bonewald, ; Karsenty & Mera, ; Maurel, Jahn, & Lara‐Castillo, ), pancreas (Faienza et al, ; Shirakawa, De Jesus, & Kulkarni, ), liver (Collier, ), kidney (Vervloet et al, ), intestine (Keller & Schinke, ), stomach (McCabe & Parameswaran, ), thyroid and adrenal glands (Rockville, ), and lymphoid tissue (Sato et al, ), could contribute to a better understanding of the endocrine functions of human bone tissue (Zaidi et al, ), bone remodeling, and associated diseases (Maurel et al, ; Owen & Reilly, ). These combinations of tissue models could also be used as operative platforms for the evaluation of the efficacy, safety, and toxicity of drug candidates (Edington et al, ; Ishida, ; Kimura, Sakai, & Fujii, ; Tetsuka, Ohbuchi, & Tabata, ) and medical devices (Guan et al, ), potentially boosting research time and cost efficiency while coming into the scope of the 3Rs principles (replace, reduce, and refine). Although the opportunities offered by these models are game‐changing, published proof‐of‐concept studies and prototypes have yet to switch from technology research to actual biological, clinical, and biomedical applications (Junaid et al, ; Kimura et al, ).…”

Section: Future Challenges and Strategymentioning

confidence: 99%

“…These combinations of tissue models could also be used as operative platforms for the evaluation of the efficacy, safety, and toxicity of drug candidates (Edington et al, 2018;Ishida, 2018;Kimura, Sakai, & Fujii, 2018;Tetsuka, Ohbuchi, & Tabata, 2017) and medical devices (Guan et al, 2017), potentially boosting research time and cost efficiency while coming into the scope of the 3Rs principles (replace, reduce, and refine). Although the opportunities offered by these models are game-changing, published proof-of-concept studies and…”

Section: From Single Culture To Multiorgan Modelsmentioning

confidence: 99%

Strategy for achieving standardized bone models

Hadida

Marchat

2019

Biotech & Bioengineering

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Reliably producing functional in vitro organ models, such as organ‐on‐chip systems, has the potential to considerably advance biology research, drug development time, and resource efficiency. However, despite the ongoing major progress in the field, three‐dimensional bone tissue models remain elusive. In this review, we specifically investigate the control of perfusion flow effects as the missing link between isolated culture systems and scientifically exploitable bone models and propose a roadmap toward this goal.

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Recent Progress in Hepatocyte Culture Models and Their Application to the Assessment of Drug Metabolism, Transport, and Toxicity in Drug Discovery: The Value of Tissue Engineering for the Successful Development of a Microphysiological System

Cited by 39 publications

References 112 publications

Use of hepatocytes isolated from a liver-humanized mouse for studies on the metabolism of drugs: application to the metabolism of fentanyl and acetylfentanyl

Use of hepatocytes isolated from a liver-humanized mouse for studies on the metabolism of drugs: application to the metabolism of fentanyl and acetylfentanyl

Metabolism of Fentanyl and Acetylfentanyl in Human-Induced Pluripotent Stem Cell-Derived Hepatocytes

Strategy for achieving standardized bone models

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