19
Oct

Liver-on-a-chip and mathematical modeling for drug metabolism studies

Can organ on a chip systems be adopted for ADME and quantitative drug metabolism studies? This is a recent paper from Docci et al. from the University of Basel that use the liver on a chip from Cn-bio to estimate pharmacokinetic parameters and drug metabolism of cultured primary hepatocytes in a scaffold perfused inside multiple chips integrated in a well-plate.

Results
In this study, the seeding efficiency, quantified by the amount of albumin production, has increased in the perfused system compared to the control. In addition, by measuring drug concentration, drug clearance for different drugs was estimated. The effect of intrinsic clearance and evaporation on the media volume, drug substrate concentration, drug amount and cell to media ratio were obtained separately. Estimated intrinsic clearance by perfused liver-on-a-chip system demonstrated reasonable human translatability of the system and its application for in vitro to in vivo extrapolation (graph below). Finally, the device proved its potential contribution in the pharmaceutical industry since all the metabolites of low metabolic turnover drugs were detected. It proposes the liver-on-a-chip potential for extending the lifetime of drug-metabolizing activities.

Liver-on-a-chip and mathematical modeling for drug metabolism studies Key words: organ on a chip, microphysiological systems, tissue chips, microfluidics, liver, drug, ADME, pharmacokinetic, hepatocytes, drug metabolism, metabolite, mathematical modelling, simulation, intrinsic clearance, IVIVE, drug-drug interaction, metabolic pathway
organ on a chip, microphysiological systems, tissue chips, microfluidics, liver, drug, ADME, pharmacokinetic, hepatocytes, drug metabolism, metabolite, mathematical modelling, simulation, intrinsic clearance, IVIVE, drug-drug interaction, metabolic pathway

Method
The authors used a LC-12 plate with a micropump system; human primary hepatocytes were seeded on the scaffolds of the LC-12 plate
Fabrication method: Reproduce CN-BIO chip
Cell injection method: Seeding hepatocytes on the scaffolds of the LC-12 plates
Perfusion/refreshing method: Continuous perfusion of hepatocytes using micropump
On-chip read-outs: Microscopy

Strong points:
+Integration of mathematical modeling and experimental work for considering media evaporation in the estimation of intrinsic clearance and fraction metabolized for metabolically stable drugs
+Considering the evaporation of medium in prolonged incubation
+Easy operation of the system: integrated pumps, easy sampling and interaction with the chips
+The chips are mainly made using an inert plastic with low non-specific binding

Improvement points:
– Use of single donor hepatocytes
– No bile flow mimicking and biliary elimination
– No assessment of non-specific binding onto the device surface, specially for highly stable drugs

Conclusion and outlook
A beautiful work integrating mathematical modeling and experimental work to estimate ADME parameters using a liver on a chip platform. The system can be developed to detect active or toxic metabolites before clinical development and open its way to the pharmaceutical industry.

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Link to paper: https://pubs.rsc.org/en/content/articlelanding/2022/lc/d1lc01161h

Citation: Docci, L., et al., Exploration and application of a liver-on-a-chip device in combination with modelling and simulation for quantitative drug metabolism studies. Lab on a Chip, 2022. 22(6): p. 1187-1205.

This article is reproduced under https://creativecommons.org/licenses/by/4.0/
The images in this post were modified for better clarity (part of the chip was  deleted) and the data were processed by AZAR Innovations