Investigation of the effect of hepatic metabolism on off-target cardiotoxicity in a multi-organ human-on-a-chip system.
Investigation of the effect of hepatic metabolism on off-target cardiotoxicity in a multi-organ human-on-a-chip system.
复制标题
研究肝脏代谢对多器官人体芯片系统中脱靶心脏毒性的影响。
DOI：
10.1016/j.biomaterials.2018.07.062
复制
发表时间：
2018-11
期刊：
影响因子：
14
通讯作者：
Hickman JJ
中科院分区：
文献类型：
--
作者：
Oleaga C;Riu A;Rothemund S;Lavado A;McAleer CW;Long CJ;Persaud K;Narasimhan NS;Tran M;Roles J;Carmona-Moran CA;Sasserath T;Elbrecht DH;Kumanchik L;Bridges LR;Martin C;Schnepper MT;Ekman G;Jackson M;Wang YI;Note R;Langer J;Teissier S;Hickman JJ
化妆品测试的监管和临床前药物研究的预测性差，促使人们努力开发新的全身毒性方法。目前的体外测定不能完全代表生理学，通常缺乏异生物质代谢。在无血清培养基中使用低容量无泵系统在流动下维持含有iPSC衍生的心肌细胞和原代肝细胞的功能性人多器官系统。收缩力和电导率的功能读数使心脏功能的非侵入性研究成为可能。系统中肝细胞的存在诱导了环磷酰胺的心脏毒性作用，并由于药物代谢而降低了特非那定的心脏毒性作用，正如每种化合物的药理学所预期的那样。计算流体动力学模拟能够预测特非那定-非索非那定的药代动力学，并通过HPLC-MS进行验证。该体外平台概括了心脏和肝脏之间体内串扰的主要方面，并能够进行药理学研究，在单个体外平台中涉及两个器官。该系统能够非侵入性地读出药物及其代谢物的心脏毒性。肝毒性也可以通过生物标志物分析和代谢功能的变化来评估。在毒理学模型中整合代谢功能可以改善临床前研究中的不良反应预测，该系统也可以用于慢性研究。
Regulation of cosmetic testing and poor predictivity of preclinical drug studies has spurred efforts to develop new methods for systemic toxicity. Current in vitro assays do not fully represent physiology, often lacking xenobiotic metabolism. Functional human multi-organ systems containing iPSC derived cardiomyocytes and primary hepatocytes were maintained under flow using a low-volume pumpless system in a serum-free medium. The functional readouts for contractile force and electrical conductivity enabled the non-invasive study of cardiac function. The presence of the hepatocytes in the system induced cardiotoxic effects from cyclophosphamide and reduced them for terfenadine due to drug metabolism, as expected from each compound’s pharmacology. A computational fluid dynamics simulation enabled the prediction of terfenadine-fexofenadine pharmacokinetics, which was validated by HPLC-MS. This in vitro platform recapitulates primary aspects of the in vivo crosstalk between heart and liver and enables pharmacological studies, involving both organs in a single in vitro platform. The system enables non-invasive readouts of cardiotoxicity of drugs and their metabolites. Hepatotoxicity can also be evaluated by biomarker analysis and change in metabolic function. Integration of metabolic function in toxicology models can improve adverse effects prediction in preclinical studies and this system could also be used for chronic studies as well.
登录
查看更多内容
影响因子：
120.1
作者：
Cook, David;Brown, Dearg;Pangalos, Menelas N.
通讯作者：
Pangalos, Menelas N.
影响因子：
2.1
作者：
Baillie TA;Rettie AE
通讯作者：
Rettie AE
影响因子：
16.1
作者：
Esch, Mandy B.;Smith, Alec S. T.;Prot, Jean-Matthieu;Oleaga, Carlota;Hickman, James J.;Shuler, Michael L.
通讯作者：
Shuler, Michael L.
影响因子：
3
作者：
Chen, Chen
通讯作者：
Chen, Chen
谷胱甘肽S-转移酶P可预防小鼠环磷酰胺诱导的心脏毒性。
影响因子：
3.8
作者：
Conklin, Daniel J.;Haberzettl, Petra;Jagatheesan, Ganapathy;Baba, Shahid;Merchant, Michael L.;Prough, Russell A.;Williams, Jessica D.;Prabhu, Sumanth D.;Bhatnagar, Aruni
通讯作者：
Bhatnagar, Aruni