Evaluation of a liver microfluidic biochip to predict In vivo clearances of seven drugs in rats
Résumé
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 HNF4 alpha, 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 mu L/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.