title: 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.
authors: CNRS UMR 7338, Laboratoire de Biomécanique et Bio ingénierie, Université de Technologie de Compiègne, Compiegne, Picardie, France.
authors: Jean Matthieu
authors: JM
authors: Prot
authors: Luis
authors: L
authors: Maciel
authors: Thibault
authors: T
authors: Bricks
authors: Franck
authors: F
authors: Merlier
authors: Jérôme
authors: J
authors: Cotton
authors: Patrick
authors: P
authors: Paullier
authors: Fréderic Yves
authors: FY
authors: Bois
authors: Eric
authors: E
authors: Leclerc
mesh_terms: D000082:Acetaminophen / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D018712:Analgesics, Non-Narcotic / Q000378:metabolism* / Q000493:pharmacokinetics*; D000818:Animals; D019149:Bioreactors; D018938:Caco-2 Cells; D002478:Cells, Cultured; D004867:Equipment Design; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D046210:Microfluidic Analytical Techniques; D008954:Models, Biological; D010539:Permeability; D051381:Rats
chemical_list: D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen; C045667:acetaminophen sulfate ester
keywords: Caco-2; alternative methods; in vitro/in vivo extrapolation; liver microfluidic biochip; paracetamol; permeability; pharmacokinetic model; phase II metabolism