Microphysiological systems (MPSs) mimicking human organ function in vitro are an emerging alternative to conventional cell culture and animal models for drug development. Human-induced pluripotent stem cells (hiPSCs) have the potential to capture the diversity of human genetics and provide an unlimited supply of cells. Combining hiPSCs with microfluidics technology in MPSs offers new perspectives for drug development. Here, the integration of a newly developed liver MPS with a cardiac MPS both built with the same hiPSC line to study drug-drug interaction (DDI) is reported. As a prominent example of clinically relevant DDI, the interaction of the arrhythmogenic gastroprokinetic cisapride with the fungicide ketoconazole was investigated. As seen in patients, metabolic conversion of cisapride to non-arrhythmogenic norcisapride in the liver MPS by the cytochrome P450 enzyme CYP3A4 was inhibited by ketoconazole, leading to arrhythmia in the cardiac MPS. These results establish functional integration of isogenic hiPSC-based liver and cardiac MPSs, which allows screening for DDI, and thus drug efficacy and toxicity, in the same genetic background.

中文翻译：

---

基于hiPSC的集成肝脏和心脏微生理系统预测不安全的药物相互作用

在体外模仿人体器官功能的微生理系统（MPS）是用于药物开发的常规细胞培养和动物模型的新兴替代物。人类诱导的多能干细胞（hiPSC）具有捕获人类遗传学多样性并无限供应细胞的潜力。将hiPSC与MPS中的微流控技术相结合，为药物开发提供了新的视角。在此，报道了新开发的肝脏MPS与心脏MPS的集成，两者均使用相同的hiPSC系构建，以研究药物相互作用（DDI）。作为临床相关DDI的一个突出例子，研究了致心律失常的胃动动力学西沙必利与杀菌剂酮康唑的相互作用。如患者所见，酮康唑抑制了细胞色素P450酶CYP3A4在肝脏MPS中将西沙必利代谢转化为非心律失常性诺西沙必利，但酮康唑抑制了该代谢，从而导致心脏MPS出现心律不齐。这些结果建立了基于等基因hiPSC的肝脏和心脏MPS的功能整合，从而可以在相同的遗传背景下筛选DDI，从而筛选出药物功效和毒性。