First pass intestinal and liver metabolism of paracetamol in a microfluidic platform coupled with a mathematical modeling as a means of evaluating ADME processes in humans
Abstract
We developed a microfluidic platform to investigate paracetamol intestinal and liver first pass metabolism. This approach was coupled with a mathematical model to estimate intrinsic in vitro parameters and to predict in vivo processes. The kinetic modeling estimated the paracetamol and paracetamol sulfate permeabilities, the sulfate and glucuronide effluxes in the intestine compartment. Based on a gut model, we estimated intrinsic intestinal clearance of between 26 and 77 L/h for paracetamol in humans, a permeability of 10 L/h, and a gut availability between 0.17 and 0.53 (compared to 0.95—1 in vivo). The role played by the liver in paracetamol metabolism was estimated via in vitro intrinsic clearances of 7.6, 13.6, and 11.5 µL/min/10 6 cells for HepG2/C3a, rat primary hepatocytes, and human primary hepatocytes, respectively. Based on a parallel tube model to describe the liver, the paracetamol hepatic clearance, and the paracetamol hepatic availability in humans were estimated at 6.5 mL/min/kg of bodyweight (BDW) and 0.7, respectively (when compared to 5 mL/min/kg of BDW and 0.77 to 0.88 for in vivo values, respectively). The drug availability was predicted ranging between 0.24 and 0.41 (0.88 in vivo). The overall approach provided a first step in an integrated strategy combining in silico/in vitro methods based on microfluidic for evaluating drug absorption, distribution and metabolism processes. Biotechnol. Bioeng. 2014;111: 2027–2040. © 2014 Wiley Periodicals, Inc.
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A number of MPSs as an in vitro GLA model (GLA-MPS) have been reported, such as GLA for metabolism and inflammation axes.
“Thus far, a number of MPSs as an in vitro GLA model (GLA-MPS) have been reported, such as GLA for metabolism and inflammation axess.3,7- 11”
From Gut-liver-axis microphysiological system for studying cellular fluidic shear stress and inter-tissue interaction (2022) · cites this paper as [3]
GLA regulates the absorption/prevention of exogenous agents at the gut barrier and metabolic processes in the liver.
“that regulates the absorption/prevention of exogenous agents at the gut barrier and metabolic processes in the liver.2,3”
From Gut-liver-axis microphysiological system for studying cellular fluidic shear stress and inter-tissue interaction (2022) · cites this paper as [3]
Reported GLA-MPSs showed better predictive capabilities of organ-to-organ interaction compared to normal static cell-culture models.
“They showed better predictive capabilities of organ to organ interaction, compared to normal static cell-culture models.”
From Gut-liver-axis microphysiological system for studying cellular fluidic shear stress and inter-tissue interaction (2022) · cites this paper as [3]
In other GLA-MPSs, the exchange ratio is approximately 0.25% to 1% in 1 min.
“In other GLA-MPSs, 3,7 the exchange ratio is approximately 0.25% to 1% in 1 min.”
From Gut-liver-axis microphysiological system for studying cellular fluidic shear stress and inter-tissue interaction (2022) · cites this paper as [3]
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- Authors
- Prot, J. M., Maciel, L., Bricks, T., Merlier, F., Cotton, J., Paullier, P., Bois, F. Y., & Leclerc, E.
- Affiliations
- CNRS UMR 7338 Laboratoire de Biomécanique et Bio ingénierie, Université de Technologie de Compiègne Compiegne Picardie France
- CNRS EA Laboratoire de Génie enzymatique et Cellulaire, Université de Technologie de Compiègne Compiegne Picardie France
- Profilomic Boulogne‐Billancourt Ile de France France
- INERIS Unité Modèles pour la toxicologie (METO) Verneuil‐en‐Halatte Picardie France
- Venue
- Biotechnology and Bioengineering
- Publisher
- Wiley
- Published
- 2014-06-24
- Volume
- 111
- Issue
- 10
- Pages
- 2027-2040
- ISSN
- 0006-3592
- 1097-0290
- Cited by
- 89
- References
- 1
- Language
- en
- Funders
- Fondation pour la Recherche et l'Innovation” from the Université de Technologie in Compiègne (ToxOnChip project)
- ERASMUS exchange program
- 189-post Grenelle program via the Activism project
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