Sorbonne Universités, FRE CNRS 3580, Génie Enzymatique et Cellulaire, Université de Technologie de Compiègne, 60205 Compiègne Cedex, France.
Analyst. 2017 Sep 25;142(19):3747-3757. doi: 10.1039/c7an00973a.
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.
微流控肝生物芯片与质谱仪相连，实时检测肝细胞的药物代谢。肝细胞在生物芯片中培养 35 小时。生物芯片被放置在一个小型孵育器中，孵育器可以控制温度和 CO2 浓度。生物芯片与质谱仪、蠕动泵和培养基储存器串联连接。质谱仪的注射每 10 分钟进行一次，持续 11 小时。研究了咪达唑仑、非那西汀、奥美拉唑、右美沙芬、瑞格列奈、罗苏伐他汀、甲苯磺丁脲和咖啡因的代谢情况。我们监测了奥美拉唑砜、羟奥美拉唑、瑞格列奈葡萄糖醛酸、罗苏伐他汀内酯、右美沙芬、1-羟基咪达唑仑、4-羟基咪达唑仑、1,4-羟基咪达唑仑、对乙酰氨基酚和 1,3-甲基黄嘌呤的出现。虽然观察到了这些，但未检测到羟甲苯磺丁脲、3-甲氧基吗啡和咪达唑仑葡萄糖醛酸、羟瑞格列奈。基于药代动力学模型，我们计算了考虑到灌注回路吸附的体外固有清除率。然后，使用肝脏器官模型，我们将体外固有清除率外推到体内清除率。估计的体内清除率与咪达唑仑、右美沙芬、非那西汀、甲苯磺丁脲和咖啡因在大鼠体内的文献数据一致。罗苏伐他汀、奥美拉唑和瑞格列奈的预测低估了体内数据。
