New technologies in drug metabolism and toxicity screening: organ-to-organ interaction

Bhushan, Abhinav; Martucci, Nicole J.; Usta, O. Berk; Yarmush, Martin L.

doi:10.1517/17425255.2016.1162292

Cited by 19 publications

(8 citation statements)

References 15 publications

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“…One of the limitations is the difficulty to perform long-term cultures (≥7 days) due to the propensity of pHeps to dedifferentiate in vitro within a few days, causing them to lose hepatocyte-specific functions (Hewitt et al, 2007;Rowe et al, 2013) and no longer accurately represent the biology of the liver. Co-cultures of pHeps with endothelial cells and/or fibroblasts, as well as recent advances in long-term cultures of pHeps, might overcome these limitations (Nahmias et al, 2006;Xiang et al, 2019), but not the shortage of donor livers (Fraczek et al, 2013;Griffith et al, 2014), resulting in high cost and considerable genetic and functional variation of commercial pHeps (Bhushan et al, 2016). These variations alone make interlaboratory comparisons nearly impossible.…”

Section: Introductionmentioning

confidence: 99%

Integrated Isogenic Human Induced Pluripotent Stem Cell–Based Liver and Heart Microphysiological Systems Predict Unsafe Drug–Drug Interaction

et al. 2021

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Three-dimensional (3D) microphysiological systems (MPSs) mimicking human organ function in vitro are an emerging alternative to conventional monolayer cell culture and animal models for drug development. Human induced pluripotent stem cells (hiPSCs) have the potential to capture the diversity of human genetics and provide an unlimited supply of cells. Combining hiPSCs with microfluidics technology in MPSs offers new perspectives for drug development. Here, the integration of a newly developed liver MPS with a cardiac MPS—both created with the same hiPSC line—to study drug–drug interaction (DDI) is reported. As a prominent example of clinically relevant DDI, the interaction of the arrhythmogenic gastroprokinetic cisapride with the fungicide ketoconazole was investigated. As seen in patients, metabolic conversion of cisapride to non-arrhythmogenic norcisapride in the liver MPS by the cytochrome P450 enzyme CYP3A4 was inhibited by ketoconazole, leading to arrhythmia in the cardiac MPS. These results establish integration of hiPSC-based liver and cardiac MPSs to facilitate screening for DDI, and thus drug efficacy and toxicity, isogenic in the same genetic background.

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Section: Introductionmentioning

confidence: 99%

Integrated Isogenic Human Induced Pluripotent Stem Cell–Based Liver and Heart Microphysiological Systems Predict Unsafe Drug–Drug Interaction

et al. 2021

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“…One of the limitations is the difficulty to perform long-term cultures (≥7 days) due to the propensity of pHeps to dedifferentiate in vitro within a few days, causing them to lose hepatocyte-specific functions 17,18 and no longer represent accurately the biology of the liver. Recent advances in long-term cultures of pHeps might overcome these limitations 19 but not the shortage of donor livers 20,21 , resulting in high cost and considerable genetic and functional variation of commercial pHeps 22 . These variations alone make interlaboratory comparisons nearly impossible.…”

Section: Introductionmentioning

confidence: 99%

Integrated hiPSC-based liver and heart microphysiological systems predict unsafe drug-drug interaction

Lee-Montiel

Laemmle

Dumont

et al. 2020

Preprint

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Microphysiological systems (MPSs) mimicking human organ function in vitro are an emerging alternative to conventional cell culture and animal models for drug development. Human induced pluripotent stem cells (hiPSCs) have the potential to capture the diversity of human genetics and provide an unlimited supply of cells. Combining hiPSCs with microfluidics technology in MPSs offers new perspectives for drug development. Here, the integration of a newly developed liver MPS with a cardiac MPS-both built with the same hiPSC line-to study drug-drug interaction (DDI) is reported. As a prominent example of clinically relevant DDI, the interaction of the arrhythmogenic gastroprokinetic cisapride with the fungicide ketoconazole was investigated. As seen in patients, metabolic conversion of cisapride to nonarrhythmogenic norcisapride in the liver MPS by the cytochrome P450 enzyme CYP3A4 was inhibited by ketoconazole, leading to arrhythmia in the cardiac MPS. These results establish functional integration of isogenic hiPSC-based liver and cardiac MPSs, which allows screening for DDI, and thus drug efficacy and toxicity, in the same genetic background.

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“…Recent advances in microfluidic techniques have led to the development of in vitro tissues models with improved tissues morphology and function. And it shows significant promise for drug assessment compared to conventional research [ 10 , 11 , 12 , 13 , 14 ]. In PK studies, the intestine is important as it is closely related to the bioavailability and bioactivity of ingested substances [ 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Modeling Pharmacokinetic Profiles for Assessment of Anti-Cancer Drug on a Microfluidic System

et al. 2020

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The pharmacokinetic (PK) properties of drug, which include drug absorption and excretion, play an important role in determining the in vivo pharmaceutical activity. However, current in vitro systems that model PK profiles are often limited by the in vivo-like concentration profile of a drug. Herein, we present a perfused and multi-layered microfluidic chip system to model the PK profile of anti-cancer drug 5-FU in vitro. The chip device contains two layers of culture channels sandwiched by a porous membrane, which allows for drug exposure and diffusion between the two channels. The integration of upper intestine cells (Caco-2) and bottom targeted cells within the device enables the generation of loading and clearance portions of a PK curve under peristaltic flow. Fluorescein as a test molecule was initially used to generate a concentration-time curve, investigating the effects of parameters of flow rate, administration time, and initial concentration on dynamic drug concentration profiles. Furthermore, anti-cancer drug 5-FU was performed to assess its pharmaceutical activity on target cells (human lung adenocarcinoma cells or human pulmonary alveolar epithelial cells) using different drug administration regimens. A dynamic, in vivo-like 5-FU exposure refers to PK profile regimen, led to generate a lower drug concentration (dynamically fluctuate from 0 to 1 μg/mL affected by absorption) compared to the constant exposure. Moreover, the PK profile regimen alleviates the drug-induced cytotoxicity on target cells. These results demonstrate the feasibility of determining the PK profiles using this microfluidic system with in vivo-like drug administration regimens. This established system may provide a powerful platform for the prediction of drug safety and effectiveness in the pharmaceutical research.

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New technologies in drug metabolism and toxicity screening: organ-to-organ interaction

Cited by 19 publications

References 15 publications

Integrated Isogenic Human Induced Pluripotent Stem Cell–Based Liver and Heart Microphysiological Systems Predict Unsafe Drug–Drug Interaction

Integrated Isogenic Human Induced Pluripotent Stem Cell–Based Liver and Heart Microphysiological Systems Predict Unsafe Drug–Drug Interaction

Integrated hiPSC-based liver and heart microphysiological systems predict unsafe drug-drug interaction

Modeling Pharmacokinetic Profiles for Assessment of Anti-Cancer Drug on a Microfluidic System

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