Evaluation of a liver microfluidic biochip to predict in vivo clearances of seven drugs in rats

Journal of Pharmaceutical Sciences
Régis BaudoinEric Leclerc

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 predict...Continue Reading

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Citations

Aug 6, 2014·Nature Biotechnology·Sangeeta N Bhatia, Donald E Ingber
Nov 26, 2015·Analytical Chemistry·Damith E W PatabadigeChristopher T Culbertson
Jul 30, 2015·Journal of Controlled Release : Official Journal of the Controlled Release Society·Kathleen A FitzgeraldCaitriona M O' Driscoll
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Dec 15, 2016·Micromachines·Giovanni Stefano UgoliniMarco Rasponi
Aug 8, 2020·Chemical Society Reviews·María Virumbrales-MuñozDavid J Beebe

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