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Updated: Jul 13, 2026
Visualization and Analysis of Blood Flow and Oxygen Consumption in Hepatic Microcirculation: Application to an Acute Hepatitis Model
Published on: August 4, 2012
An oxygen-permeable, stirrer-pump-integrated liver-heart microphysiological system enables time-resolved analysis in
Shinichiro Horiuchi1, Kiyoshi Oka2, Kenta Shinha3
1Division of Pharmacology, National Institute of Health Sciences, Kawasaki, Kanagawa, 210-9501, Japan.
Abstract:
Predicting metabolism-dependent drug toxicity encompassing both the bioactivation and detoxification processes remains a critical challenge in preclinical safety evaluations. Conventional cardiomyocyte-only assays frequently misclassify compounds such as terfenadine, which require hepatic metabolism to attenuate cardiotoxicity. Current microphysiological systems (MPS) have practical limitations, such as insufficient hepatocyte oxygenation and complex external fluidic setups. We developed a liver-heart co-culture system that integrates three-dimensional human iPS cell-derived engineered heart tissues (hiPSC-EHTs) and cryopreserved primary human hepatocytes (PHHs), using a modified BioStellar™ Plate-a tubeless, stirrer-pump-integrated microfluidic device customized with an oxygen-permeable membrane. Using this system, we evaluated the cardiotoxicity of terfenadine in hiPSC-EHT monocultures and liver-heart co-cultures. Terfenadine exposure induced marked contractile dysfunction in hiPSC-EHT monocultures, whereas co-culturing with PHHs significantly attenuated this effect. Functional monitoring revealed time- and dose-dependent recovery, consistent with a largely reversible pharmacological mechanism. Drug concentration analysis by LC-MS/MS showed a marked increase in the formation of the primary metabolite fexofenadine, in the co-culture system, which was consistent with the reduced cardiotoxic potential of this metabolite. Gene expression analysis confirmed the presence of hepatic CYP3A4, which supports its predominant role in metabolic detoxification. This study demonstrated that a tubeless, stirrer-pump-integrated system with sustained hepatocyte function enables time-resolved evaluation of pharmacokinetic-pharmacodynamic relationships of metabolism-dependent cardiotoxicity on a single platform. This proof-of-concept approach suggests a potential improvement in the translational predictability of human-relevant, metabolism-dependent cardiotoxicity by enabling integrated evaluation of pharmacokinetic and pharmacodynamic responses. These findings highlight the utility of this system as a simple and scalable alternative to conventional perfusion-based MPS.
Insights
This study developed a liver-heart co-culture system to predict metabolism-dependent drug toxicity. The new system accurately assessed terfenadine cardiotoxicity, showing improved preclinical safety evaluation potential.
Area of Science:
- Toxicology
- Drug Metabolism
- Cardiovascular Research
Background:
- Metabolism-dependent drug toxicity prediction is challenging.
- Existing microphysiological systems (MPS) have limitations in hepatocyte function and setup complexity.
- Terfenadine cardiotoxicity is often misclassified by cardiomyocyte-only assays.
Purpose of the Study:
- To develop and validate a novel liver-heart co-culture system for predicting metabolism-dependent cardiotoxicity.
- To evaluate the cardiotoxicity of terfenadine using this integrated system.
- To assess the system's ability to capture pharmacokinetic-pharmacodynamic relationships.
Main Methods:
- Co-culture of human induced pluripotent stem cell-derived engineered heart tissues (hiPSC-EHTs) and primary human hepatocytes (PHHs).
- Utilized a modified, tubeless, stirrer-pump-integrated microfluidic device with an oxygen-permeable membrane.
- Assessed terfenadine cardiotoxicity via functional monitoring and drug concentration analysis (LC-MS/MS).
Main Results:
- Co-culturing with PHHs significantly attenuated terfenadine-induced cardiotoxicity in hiPSC-EHTs.
- Increased formation of the less toxic metabolite fexofenadine was observed in the co-culture system.
- Gene expression confirmed CYP3A4 activity, crucial for terfenadine detoxification.
Conclusions:
- The developed liver-heart co-culture system enables accurate, time-resolved evaluation of metabolism-dependent cardiotoxicity.
- This system offers improved translational predictability for drug safety assessments.
- It serves as a scalable and simpler alternative to conventional perfusion-based MPS.
