Abstract：
In the evolving field of drug discovery and development, multiorgans-on-a-chip and microphysiological systems are gaining popularity owing to their ability to emulate in vivo biological environments. Among the various gut-liver-on-a-chip systems for studying oral drug absorption, the chip developed in this study stands out with two distinct features: incorporation of perfluoropolyether (PFPE) to effectively mitigate drug sorption and a unique enterohepatic single-passage system, which simplifies the analysis of first-pass metabolism and oral bioavailability. By introducing a bolus drug injection into the liver compartment, hepatic extraction alone could be evaluated, further enhancing our estimation of intestinal availability. In a study on midazolam (MDZ), PFPE-based chips showed more than 20-times the appearance of intact MDZ in the liver compartment effluent compared to PDMS-based counterparts. Notably, saturation of hepatic metabolism at higher concentrations was confirmed by observations when the dose was reduced from 200 μM to 10 μM. This result was further emphasized when the metabolism was significantly inhibited by the coadministration of ketoconazole. Our chip, which is designed to minimize the dead volume between the gut and liver compartments, is adept at sensitively observing the saturation of metabolism and the effect of inhibitors. Using genome-edited CYP3A4/UGT1A1-expressing Caco-2 cells, the estimates for intestinal and hepatic availabilities were 0.96 and 0.82, respectively; these values are higher than the known human in vivo values. Although the metabolic activity in each compartment can be further improved, this gut-liver-on-a-chip can not only be used to evaluate oral bioavailability but also to carry out individual assessment of both intestinal and hepatic availability.
摘要：
在不断发展的药物发现和开发领域，芯片上的多器官和微生理系统由于能够模拟体内生物环境而越来越受欢迎。在用于研究口服药物吸收的各种肠-肝芯片系统中，在这项研究中开发的芯片突出了两个不同的特征：全氟聚醚（PFPE）的掺入，以有效地减轻药物吸附和独特的肠肝单通道系统，这简化了首过代谢和口服生物利用度的分析。通过将推注药物引入肝室，可以单独评估肝脏提取，进一步增强我们对肠道利用率的估计。在对咪达唑仑（MDZ）的研究中，与基于PDMS的对应物相比，基于PFPE的芯片在肝室流出物中显示出完整MDZ的外观是其20倍以上。值得注意的是,当剂量从200μM减少到10μM时,观察证实了较高浓度的肝代谢饱和.当通过酮康唑的共同给药显著抑制代谢时,该结果被进一步强调。我们的芯片,它的设计目的是最小化肠道和肝脏之间的死体积，擅长灵敏地观察代谢的饱和和抑制剂的作用。使用基因组编辑的CYP3A4/UGT1A1表达Caco-2细胞，肠和肝的有效性估计值分别为0.96和0.82;这些值高于已知的人类体内值。虽然每个隔室的代谢活性可以进一步提高，这种肠-肝脏芯片不仅可用于评估口服生物利用度,还可用于对肠道和肝脏的可利用性进行个体评估.
