An Intestine/Liver Microphysiological System for Drug Pharmacokinetic and Toxicological Assessment

Talita  Miguel Marin; Nathalia  de Carvalho Indolfo; Silvana  Aparecida Rocco; Murilo de Carvalho; Marilia  Meira Dias; Graziele Izalina Vasconcelos Bento; Leandro Oliveira Bortot; Desir&#233;e Cigaran Schuck; M&#225;rcio Lorencini; Eduardo Pagani

doi:10.3791/60184

An Intestine/Liver Microphysiological System for Drug Pharmacokinetic and Toxicological Assessment

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Chemistry

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JoVE Journal Chemistry

An Intestine/Liver Microphysiological System for Drug Pharmacokinetic and Toxicological Assessment

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08:59 min

December 3, 2020

DOI: 10.3791/60184-v

Talita Miguel Marin¹, Nathalia de Carvalho Indolfo⁴, Silvana Aparecida Rocco¹, Murilo de Carvalho^1,2, Marilia Meira Dias¹, Graziele Izalina Vasconcelos Bento¹, Leandro Oliveira Bortot¹, Desirée Cigaran Schuck³, Márcio Lorencini³, Eduardo Pagani¹

¹Brazilian Biosciences National Laboratory (LNBio),Brazilian Center for Research in Energy and Materials (CNPEM), ²Brazilian Synchrotron Light Laboratory (LNLS),Brazilian Center for Research in Energy and Materials (CNPEM), ³Grupo Boticário, ⁴Institute of Biology,University of Campinas

Overview

This study investigates the use of a microphysiological system (MPS) incorporating intestine and liver organoids to assess the pharmacokinetics and toxicological properties of acetaminophen (APAP). The article details the methodologies for organoid production and the necessary analyses to validate tissue functionality.

Key Study Components

Area of Science

Microphysiological systems
Pharmacokinetics
Toxicology

Background

Microphysiological systems emulate human body responses.
They can potentially replace animal testing.
These systems enhance predictive power of in vitro methods.
They reduce costs and time in pharmacological studies.

Purpose of Study

To evaluate the effects of acetaminophen using organoid models.
To validate the functionality of intestinal and liver organoids.
To improve understanding of drug metabolism and toxicity.

Methods Used

Preparation of organoids from intestinal and liver tissues.
Administration of acetaminophen in the MPS.
Assessment of pharmacokinetic properties.
Evaluation of toxicological responses in the organoids.

Main Results

Successful integration of organoids into the microphysiological system.
Demonstrated pharmacokinetic profiles of acetaminophen.
Identified toxicological responses in liver and intestinal organoids.
Validated tissue functionality through various analyses.

Conclusions

The MPS effectively models human responses to acetaminophen.
Organoid systems can provide insights into drug metabolism.
This approach may reduce reliance on animal testing in pharmacological research.

Frequently Asked Questions

What is a microphysiological system?

A microphysiological system is a laboratory model that mimics the physiological responses of human organs to various treatments.

How does this study contribute to drug testing?

This study provides a framework for using organoid models to assess drug metabolism and toxicity, potentially replacing animal models.

What are organoids?

Organoids are three-dimensional structures derived from stem cells that replicate some functions of real organs.

Why is acetaminophen used in this study?

Acetaminophen is a common drug whose pharmacokinetics and toxicity are well-studied, making it a suitable candidate for this research.

What are the benefits of using organoids in research?

Organoids provide a more accurate representation of human biology compared to traditional cell cultures, improving the reliability of research findings.

What future applications could arise from this research?

Future applications may include personalized medicine approaches and improved drug development processes.

We exposed a microphysiological system (MPS) with intestine and liver organoids to acetaminophen (APAP). This article describes the methods for organoid production and APAP pharmacokinetic and toxicological property assessments in the MPS. It also describes the tissue functionality analyses necessary to validate the results.

Microphysiological systems have the ability to emulate pharmacokinetic and the toxicological response of the human body to specific treatments of interests. Microphysiological systems have the potential to replace animal tests as their use can improve the predictive power of in vitro methods and reduce the cost and time of pharmacokinetical and toxicological studies. 24 hours before the test substance administration, split an 800 microliter aliquot of William ES medium between the larger and smaller compartments of the two organ chip, and aspirate the basolateral and apical medium from each intestinal barrier equivalent in the prepared 24 well plates.

Using sterile forceps, integrate one insert per two organ chip circuit into the larger compartment and add 200 microliters of DMEMS to the apical side. Using wide bore tips, integrate 20 liver equivalents per circuit into the smaller compartment of the two organ chip and connect the system to the control unit. Then connect the control unit to a pressurized air supply and set the pressure to approximately plus or minus 300 bars and a pumping frequency of 0.3 Hertz.

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