Bricks T.,CNRS Biomechanical Engineering Laboratory |
Hamon J.,CNRS Biomechanical Engineering Laboratory |
Fleury M.J.,CNRS Biomechanical Engineering Laboratory |
Jellali R.,CNRS Biomechanical Engineering Laboratory |
And 7 more authors.
Biopharmaceutics and Drug Disposition | Year: 2015
A new in vitro microfluidic platform (integrated insert dynamic microfluidic platform, IIDMP) allowing the co-culture of intestinal Caco-2 TC7 cells and of human primary hepatocytes was used to test the absorption and first-pass metabolism of two drugs: phenacetin and omeprazole. The metabolism of these drugs by CYP1A2, CYP2C19 and CYP3A4 was evaluated by the calculation of bioavailabilities and of intrinsic clearances using a pharmacokinetic (PK) model. To demonstrate the usefulness of the device and of the PK model, predictions were compared with in vitro and in vivo results from the literature. Based on the IIDMP experiments, hepatic in vivo clearances of phenacetin and omeprazole in the IIDMP were predicted to be 3.10 ± 0.36 and 1.46 ± 0.25 ml/min/kg body weight, respectively. This appeared lower than the in vivo observed data with values ranging between 11.9-19.6 and 5.8-7.5 ml/min/kg body weight, respectively. Then the calculated hepatic and intestinal clearances led to predicting an oral bioavailability of 0.85 and 0.77 for phenacetin and omeprazole versus 0.92 and 0.78 using separate data from the simple monoculture of Caco-2 TC7 cells and hepatocytes in Petri dishes. When compared with the in vivo data, the results of oral bioavailability were overestimated (0.37 and 0.71, respectively). The feasibility of co-culture in a device allowing the integration of intestinal absorption, intestinal metabolism and hepatic metabolism in a single model was demonstrated. Nevertheless, further experiments with other drugs are needed to extend knowledge of the device to predict oral bioavailability and intestinal first-pass metabolism. © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.
Investigation of the hepatotoxicity of flutamide: Pro-survival/apoptotic and necrotic switch in primary rat hepatocytes characterized by metabolic and transcriptomic profiles in microfluidic liver biochips
Legendre A.,CNRS Biomechanical Engineering Laboratory |
Jacques S.,French Institute of Health and Medical Research |
Dumont F.,French Institute of Health and Medical Research |
Cotton J.,Profilomic |
And 3 more authors.
Toxicology in Vitro | Year: 2014
We investigated the effects of the liver damage induced by flutamide in primary rat hepatocytes using liver microfluidic biochips. Flutamide is a non-steroidal anti-androgenic drug. Two flutamide concentrations, 10. μM and 100. μM, were used to expose the hepatocytes for 24. h under perfusion. Thanks to the maintenance of hepatocyte differentiation phenotype and to the biotransformation performance in the microfluidic cultures, the metabolic ratio analysis of hydroxyflutamide, flutamide-gluthatione and hydroxyflutamide-gluthatione productions demonstrated saturation of the drug's biotransformation process and the maintenance of a high level of flutamide at 100. μM when compared to 10. μM. A microarray analysis comparing flutamide (10 or 100. μM) with controls revealed a common response for both concentrations illustrated by modulating the expression of the mRNA of genes associated with mitochondrial perturbation, of the proliferator-activated receptors (Ppar) signaling, lipid and fatty acid metabolism, antioxidant defense, and cell death pathways, consistently with in vitro and in vivo reports. Additionally to literature reports, our integration of the transcriptomic profiles demonstrated a specific dose dependent response. We found at 10. μM a typical pro-survival/apoptosis network activation (through IGF/PDGFD upstream route and via a downstream up regulation in CREB5, BCL2, IKBKG routes in the PI3K/signaling). We also found a down regulation of mRNA levels in sugar and amino acid metabolism pathways. At 100. μM a typical necrosis switch was observed associated with a down regulation of the tight junctions' pathway, a cellular aggregation and a reduction of the cell viability. Altogether our data demonstrated the potential and the sensitivity of our liver microfluidic cultures to evaluate xenobiotic toxicity by improving in vitro analysis and reproducing both in vitro and in vivo results. Finally, we proposed two integrated synthetic networks to describe the response of rat hepatocytes to both exposure concentrations of flutamide. © 2014 Elsevier Ltd.
Prot J.M.,CNRS Biomechanical Engineering Laboratory |
Maciel L.,CNRS Biomechanical Engineering Laboratory |
Bricks T.,CNRS Biomechanical Engineering Laboratory |
Merlier F.,Compiegne University of Technology |
And 5 more authors.
Biotechnology and Bioengineering | Year: 2014
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 77L/h for paracetamol in humans, a permeability of 10L/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 11.5μL/min/106 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 6.5mL/min/kg of bodyweight (BDW) and 0.7, respectively (when compared to 5mL/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. © 2014 Wiley Periodicals, Inc.
Profilomic | Date: 2011-12-13
Pharmaceutical and veterinary preparations for the prevention of metabolic or genetic diseases or of diseases having metabolic effects; sanitary preparations for medical use; dietetic foods adapted for medical use; food for babies; medicated bath preparations; chemical preparations for medical or pharmaceutical use, namely, for use in preventing metabolic-related or genetic diseases; medicinal herbs. Scientific evaluations, assessments and research in the fields of science and technology provided by engineers; design and development of computer hardware and software; product research and development for others; engineering services, particularly technical project planning and design engineering of lines for the processing of web products; development, design, installation, maintenance, updating or rental of software; computer programming; consultancy in the field of computer hardware; data conversion of computer programs and data other than physical conversion; conversion of data or documents from physical to electronic media.
Cotton J.,CEA Saclay Nuclear Research Center |
Leroux F.,Profilomic |
Broudin S.,Profilomic |
Marie M.,Profilomic |
And 5 more authors.
Journal of Agricultural and Food Chemistry | Year: 2014
Analytical methods for food control are mainly focused on restricted lists of well-known contaminants. This paper shows that liquid chromatography-high-resolution mass spectrometry (LC/ESI-HRMS) associated with the data mining tools developed for metabolomics can address this issue by enabling (i) targeted analyses of pollutants, (ii) detection of untargeted and unknown xenobiotics, and (iii) detection of metabolites useful for the characterization of food matrices. A proof-of-concept study was performed on 76 honey samples. Targeted analysis indicated that 35 of 83 targeted molecules were detected in the 76 honey samples at concentrations below regulatory limits. Furthermore, untargeted metabolomic-like analyses highlighted 12 chlorinated xenobiotics, 1 of which was detected in lavender honey samples and identified as 2,6-dichlorobenzamide, a metabolite of dichlobenil, a pesticide banned in France since 2010. Lastly, multivariate statistical analyses discriminated honey samples according to their floral origin, and six discriminating metabolites were characterized thanks to the MS/MS experiments. © 2014 American Chemical Society.