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Human Liver Microphysiological System for Assessing Drug-Induced Liver Toxicity In Vitro
Published on: January 31, 2022
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Quantitative Assessment of Population Variability in Hepatic Drug Metabolism Using a Perfused Three-Dimensional Human
N Tsamandouras1, T Kostrzewski1, C L Stokes1
1Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts (N.T., L.G.G., M.C.); CN Bio Innovations, Hertfordshire, United Kingdom (T.K., D.J.H.); and Stokes Consulting, Redwood City, California (C.L.S.).
The Journal of Pharmacology and Experimental Therapeutics
|October 21, 2016
Summary
This study quantifies drug metabolism variability in human liver models, linking in vitro data to in vivo pharmacokinetics. Findings highlight microphysiological systems
Area of Science:
- Pharmacology and Toxicology
- Drug Metabolism and Pharmacokinetics
- Biotechnology and Bioengineering
Background:
- Hepatic drug metabolism exhibits significant inter-individual variability, impacting drug efficacy and safety.
- Accurate prediction of in vitro-in vivo drug behavior is crucial for efficient drug development.
- Human liver microphysiological systems offer a promising platform for studying drug metabolism.
Purpose of the Study:
- To characterize population variability in hepatic drug metabolism using a human liver microphysiological system.
- To integrate in vitro metabolic data with modeling and simulation for in vitro-in vivo translation.
- To demonstrate the utility of microphysiological systems in predicting pharmacokinetic variability.
Main Methods:
- Cryopreserved hepatocytes from five donors were cultured in a perfused 3D liver microphysiological system.
- Metabolic depletion, metabolite formation, gene expression (90 metabolism genes), and viability markers were measured.
- Mixed-effects modeling analyzed drug depletion data; population physiologically based pharmacokinetic models were developed.
Main Results:
- Substantial interdonor variability was observed in gene expression, drug metabolism, and hepatocyte functions.
- Interdonor variability in intrinsic metabolic clearance ranged from 24.1% (phenacetin) to 66.8% (propranolol).
- Albumin, urea, LDH, and CYP450 mRNA levels predicted in vitro metabolic clearance; in vitro data correlated with in vivo values.
Conclusions:
- This study is the first to assess population variability in drug metabolism using a microphysiological system.
- The findings support the use of liver microphysiological systems for predicting in vivo drug metabolism and population variability.
- Integrating microphysiological system data with pharmacokinetic modeling advances drug development processes.
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