title: Evaluation of a liver microfluidic biochip to predict in vivo clearances of seven drugs in rats.
abstract: We investigated metabolic clearances of phenacetin, midazolam, propranolol, paracetamol, tolbutamide, caffeine, and dextromethorphan by primary rat hepatocytes cultivated in microfluidic biochips. The levels of mRNA of the HNF4α, PXR, AHR, CYP3A1, and CYP1A2 genes were enhanced in the biochip cultures when compared with postextraction levels. We measured a high and rapid adsorption on the biochip walls and inside the circuit for dextromethorphan and midazolam, a moderate adsorption for phenacetin and propranolol, and a low adsorption for caffeine, tolbutamide, and paracetamol. Drug biotransformations were demonstrated by the formations of specific metabolites such as paraxanthyne (caffeine), paracetamol (phenacetin), 1-OH midazolam (midazolam), paracetamol sulfate (paracetamol and phenacetin), and dextrorphan (dextromethorphan). We used a pharmacokinetic model to estimate the adsorption and in vitro intrinsic drug clearance values. We calculated in vitro intrinsic clearance values of 0.5, 3, 12.5, 83, 100, 160, and 900 μL/min per 10(6) cells for the tolbutamide, caffeine, paracetamol, dextromethorphan, phenacetin, midazolam, and propranolol, respectively. A second model describing the liver as a well-stirred compartment predicted in vivo hepatic clearances of 0.1, 13.8, 30, 44.1, 61, 72, 85, and 61 mL/min per kg of body mass for the tolbutamide, caffeine, paracetamol, midazolam, dextromethorphan, phenacetin, and propranolol, respectively. These values appeared consistent with previously reported data.
authors: CNRS, UMR 7338, Laboratoire de Biomécanique et Bio ingénierie, Université de Technologie de Compiègne, Compiègne, France.
authors: Regis
authors: R
authors: Baudoin
authors: Audrey
authors: A
authors: Legendre
authors: Sebastien
authors: S
authors: Jacques
authors: Jerome
authors: J
authors: Cotton
authors: Frederic
authors: F
authors: Bois
authors: Eric
authors: E
authors: Leclerc
mesh_terms: D000465:Algorithms; D000818:Animals; D019149:Bioreactors; D002452:Cell Count; D002470:Cell Survival; D008401:Gas Chromatography-Mass Spectrometry; D022781:Hepatocytes / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D008838:Microcomputers; D046210:Microfluidic Analytical Techniques / Q000379:methods*; D044085:Microfluidics; D015233:Models, Statistical; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010599:Pharmacokinetics; D061251:Primary Cell Culture; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D012997:Solvents
chemical_list: D004364:Pharmaceutical Preparations; D012333:RNA, Messenger; D012997:Solvents
keywords: drug metabolism; hepatic clearance; in vitro model; mathematical model; microfluidic biochips; pharmacokinetics; rat hepatocytes