Emerging<i>In Vitro</i>Liver Technologies for Drug Metabolism and Inter-Organ Interactions

Bale, Shyam Sundhar; Moore, Laura; Yarmush, Martin L.; Jindal, Rohit

doi:10.1089/ten.teb.2016.0031

Cited by 40 publications

(42 citation statements)

References 70 publications

(82 reference statements)

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“…PHHs are essential tools in the assessment of drug transporters, a feature of drug metabolism that subcellular fraction models do not address [27, 28]. Unfortunately, PHHs lose proliferative ability in isolation and have significant variability in enzyme expression, causing cell source limitations [29]. Nevertheless, there have been a number of promising efforts to induce PPH culture expansion [30, 31].…”

Section: Biological Assessment Of Drug Metabolism In Preclinicalmentioning

confidence: 99%

“…This particular dimension of drug metabolism is logistically difficult and uneconomical in in vivo approaches. An area where in vivo models have the advantage is in multi-organ and inter-organ interactions, but innovative cell-culture systems for liver-based multi-organ models are beginning to have an impact, as reviewed by Bale et al [29]. …”

Section: Biological Assessment Of Drug Metabolism In Preclinicalmentioning

confidence: 99%

See 1 more Smart Citation

Drug Metabolism in Preclinical Drug Development: A Survey of the Discovery Process, Toxicology, and Computational Tools

Issa

Wathieu

Ojo

et al. 2017

CDM

103

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Increased R & D spending and high failure rates exist in drug development, due in part to inadequate prediction of drug metabolism and its consequences in the human body. Hence, there is a need for computational methods to supplement and complement current biological assessment strategies. In this review, we provide an overview of drug metabolism in pharmacology, and discuss the current in vitro and in vivo strategies for assessing drug metabolism in preclinical drug development. We highlight computational tools available to the scientific community for the in silico prediction of drug metabolism, and examine how these tools have been implemented to produce drug-target signatures relevant to metabolic routes. Computational workflows that assess drug metabolism and its toxicological and pharmacokinetic effects, such as by applying the adverse outcome pathway framework for risk assessment, may improve the efficiency and speed of preclinical drug development.

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Section: Biological Assessment Of Drug Metabolism In Preclinicalmentioning

confidence: 99%

Section: Biological Assessment Of Drug Metabolism In Preclinicalmentioning

confidence: 99%

Drug Metabolism in Preclinical Drug Development: A Survey of the Discovery Process, Toxicology, and Computational Tools

Issa

Wathieu

Ojo

et al. 2017

CDM

103

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“…Godoy et al (2013) reviewed in detail besides other aspects the possibilities, limitations, and pitfalls of the various liver cell models. Recently, Bale et al (2016) reviewed current liver-based multi-organ cell culture platforms primarily from a drug and metabolite perspective and highlighted the importance of cell-to-media ratio in interfacing liver models with other organ models. Further discussion on the suitability of various liver models for DoA metabolism studies can be found in the recent review article of Meyer (2016).…”

Section: Hrms For Elucidation Of the Metabolite Structures And Formatmentioning

confidence: 99%

High-resolution mass spectrometry in toxicology: current status and future perspectives

Maurer

Meyer

2016

Arch Toxicol

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This paper reviews high-resolution mass spectrometry (HRMS) approaches using time-of-flight or Orbitrap techniques for research and application in various toxicology fields, particularly in clinical toxicology and forensic toxicology published since 2013 and referenced in PubMed. In the introduction, an overview on applications of HRMS in various toxicology fields is given with reference to current review articles. Papers concerning HRMS in metabolism, screening, and quantification of pharmaceuticals, drugs of abuse, and toxins in human body samples are critically reviewed. Finally, a discussion on advantages as well as limitations and future perspectives of these methods is included.

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“…With hepatotoxicity accounting for >35% failures in drug development processes, there is a substantial need for comprehensive, predictive models capturing hepatic function, feedback and responses (Mehta, Editor, & Pinsky, ; Olson et al, ; Schuster, Laggner, & Langer, ). To obtain human‐relevant information, several in vitro cell culture systems (comprising cells and matrix materials from both animal and human sources) have been developed (Bale & Borenstein, ; Bale et al, ; Bale, Moore, Yarmush, & Jindal, ; Bjornsson et al, ; Ewart et al, ; Godoy et al, ; Greaves et al, ; Materne, Tonevitsky, & Marx, ; Soldatow, Lecluyse, Griffith, & Rusyn, ). The primary focus of in vitro hepatic cell culture systems has been primary human hepatocyte (PHH) stabilization and long‐term culture, achieved using collagen sandwich (Dunn, Tompkins, & Yarmush, ), spheroid (Messner, Agarkova, Moritz, & Kelm, ), 3D printing (Nguyen et al, ), and micropatterning (Khetani & Bhatia, ) techniques.…”

Section: Introductionmentioning

confidence: 99%

“…The primary focus of in vitro hepatic cell culture systems has been primary human hepatocyte (PHH) stabilization and long‐term culture, achieved using collagen sandwich (Dunn, Tompkins, & Yarmush, ), spheroid (Messner, Agarkova, Moritz, & Kelm, ), 3D printing (Nguyen et al, ), and micropatterning (Khetani & Bhatia, ) techniques. In addition to static systems, high‐throughput in vitro models and advanced dynamic microfluidic systems are emerging as tools to predict ADMET attributes, and disease modeling in particular (Bale et al, ; Bale, Moore, et al, ; Bhatia & Ingber, ; Ewart et al, ; Hughes, Kostrzewski, & Sceats, ; Materne et al, ). Further, these organ‐on‐chip systems have the potential to elucidate molecular and cellular phenotypes of rare diseases, and aid in drug development (Low & Tagle, ; Low & Tagle, ).…”

Section: Introductionmentioning

confidence: 99%

A thermoplastic microfluidic microphysiological system to recapitulate hepatic function and multicellular interactions

Bale

Manoppo

Thompson

et al. 2019

Biotech & Bioengineering

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Hepatic in vitro platforms ranging from multi-well cultures to bioreactors and microscale systems have been developed as tools to recapitulate cellular function and responses to aid in drug screening and disease model development. Recent developments in microfabrication techniques and cellular materials enabled fabrication of next-generation, advanced microphysiological systems (MPSs) that aim to capture the cellular complexity and dynamic nature of the organ presenting highly controlled extracellular cues to cells in a physiologically relevant context. Historically, MPSs have heavily relied on elastomeric materials in their manufacture, with unfavorable material characteristics (such as lack of structural rigidity) limiting their use in high-throughput systems. Herein, we aim to create a microfluidic bilayer model (microfluidic MPS) using thermoplastic materials to allow hepatic cell stabilization and culture, retaining hepatic functional phenotype and capturing cellular interactions. The microfluidic MPS consists of two overlapping microfluidic channels separated by a porous tissue-culture membrane that acts as a surface for cellular attachment and nutrient exchange; and an oxygen permeable material to stabilize and sustain primary human hepatocyte (PHH) culture. Within the microfluidic MPS, PHHs are cultured in the top channel in a collagen sandwich gel format with media exchange accomplished through the bottom channel. We demonstrate PHH culture for 7 days, exhibiting measures of hepatocyte stabilization, secretory and metabolic functions. In addition, the microfluidic MPS dimensions provide a reduced media-to-cell ratio in comparison with multi-well tissue culture systems, minimizing dilution and enabling capture of cellular interactions and responses in a hepatocyte-Kupffer coculture modelunder an inflammatory stimulus. Utilization of thermoplastic materials in the model and ability to incorporate multiple hepatic cells within the system is our initial step towards the development of a thermoplastic-based high-throughput microfluidic MPS platform for hepatic culture. We envision the platform to find utility in development and interrogation of disease models of the liver, multi-cellular interactions and therapeutic responses.

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EmergingIn VitroLiver Technologies for Drug Metabolism and Inter-Organ Interactions

Cited by 40 publications

References 70 publications

Drug Metabolism in Preclinical Drug Development: A Survey of the Discovery Process, Toxicology, and Computational Tools

Drug Metabolism in Preclinical Drug Development: A Survey of the Discovery Process, Toxicology, and Computational Tools

High-resolution mass spectrometry in toxicology: current status and future perspectives

A thermoplastic microfluidic microphysiological system to recapitulate hepatic function and multicellular interactions

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