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 CO₂ 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.

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通过结合肝脏生物芯片和质谱仪在线监测​​肝大鼠新陈代谢

将微流控肝生物芯片与质谱仪耦合以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。将生物芯片放置在小型培养箱中，在该培养箱中温度和CO ₂浓度得到控制。将生物芯片串行连接到质谱仪，蠕动泵和培养基储存器。每10分钟在质谱仪中进样11 h。研究了咪达唑仑，非那西丁，奥美拉唑，右美沙芬，瑞格列奈，瑞舒伐他汀，甲苯磺丁酰胺和咖啡因的代谢。我们监测了奥美拉唑砜，羟基奥美拉唑，瑞格列奈葡糖苷酸，瑞舒伐他汀内酯，右旋托芬，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-甲基黄嘌呤的外观。尽管观察到了这些，但未检出羟基甲苯磺丁酰胺，3-甲氧基吗啡喃和咪达唑仑葡糖醛酸，羟基瑞格列奈。基于药代动力学模型，我们在体外进行了计算考虑了吸附到灌注回路上的固有间隙。然后，使用肝脏器官模型，我们将体外固有清除率推断为体内清除率。估计的体内清除率与咪达唑仑，右美沙芬，非那西丁，甲苯磺丁酰胺和咖啡因的大鼠文献数据一致。罗苏伐他汀，奥美拉唑和瑞格列奈的预测低估了体内数据。