Online monitoring of hepatic rat metabolism by coupling a liver biochip and a mass spectrometer

A microfluidic liver biochip was coupled with a mass spectrometer to detect in real time the drug metabolism of hepatocytes. The hepatocytes were cultivated in the biochip for 35 h. The biochip was placed in a small-scale incubator in which the temperature and CO concentration were controlled. The b...

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Bibliographic Details
Published in:Analyst (London) 2017, Vol.142 (19), p.3747-3757
Main Authors: Merlier, Franck, Jellali, Rachid, Leclerc, Eric
Format: Article
Language:English
Subjects:
Analytical chemistry
Animals
Cells, Cultured
Chemical Sciences
Hepatocytes - metabolism
Human health and pathology
Hépatology and Gastroenterology
Life Sciences
Liver
Male
Mass Spectrometry
Microfluidic Analytical Techniques
Pharmaceutical Preparations - metabolism
Rats
Rats, Sprague-Dawley
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Summary:A microfluidic liver biochip was coupled with a mass spectrometer to detect in real time the drug metabolism of hepatocytes. The hepatocytes were cultivated in the biochip for 35 h. The biochip was placed in a small-scale incubator in which the temperature and CO concentration were controlled. The biochip was connected serially to a mass spectrometer, a peristaltic pump and a culture medium reservoir. The injection in the mass spectrometer was performed every 10 min for 11 h. The metabolism of midazolam, phenacetin, omeprazole, dextromethorphan, repaglinide, rosuvastatin, tolbutamide and caffeine was investigated. We monitored the apparition of omeprazole sulfone, hydroxy omeprazole, repaglinide glucuronide, rosuvastatin lactone, dextrorphan, 1-hydroxy midazolam, 4-hydroxy midazolam, 1,4-hydroxy midazolam, paracetamol and 1,3-methylxanthine. Although these were observed, hydroxytolbutamide, 3-methoxymorphinan and midazolam glucuronide, hydroxy repaglinide were not detected. Based on a pharmacokinetic model, we calculated in vitro intrinsic clearances in which adsorption onto the perfusion circuit was taken into account. Then, using a liver organ model, we extrapolated the in vitro intrinsic clearances to the in vivo clearances. The estimated in vivo clearances were in agreement with the literature data on rats for midazolam, dextromethorphan, phenacetin, tolbutamide and caffeine. Rosuvastatin, omeprazole and repaglinide prediction underestimated the in vivo data.
ISSN:0003-2654
1364-5528
DOI:10.1039/c7an00973a