Integrated Gut and Liver Microphysiological Systems for Quantitative In Vitro Pharmacokinetic Studies.
Integrated Gut and Liver Microphysiological Systems for Quantitative In Vitro Pharmacokinetic Studies.
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DOI：
10.1208/s12248-017-0122-4
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发表时间：
2017-09
期刊：
影响因子：
--
通讯作者：
Cirit M
中科院分区：
文献类型：
--
作者：
Tsamandouras N;Chen WLK;Edington CD;Stokes CL;Griffith LG;Cirit M
化合物的药代动力学(PK)的研究在药物开发的早期阶段是非常重要的，因此，几种体外系统被常规地用于这一目的。然而，对更逼真的体外生理模型的需求最近推动了组织工程3D培养的新兴领域，也被称为芯片上器官，或微生理系统(MPSS)。我们已经开发了一种新型的流体平台，可以互连多个MPSS，允许在多器官体外系统中进行PK研究，同时收集高含量的定量数据。该平台被用来将肠道和肝脏的MPS在持续的交流中整合在一起，并同时研究人类口服药物后发生的不同的PK过程(如肠道通透性、肝脏代谢)。对组织特异性表型指标的测量表明，肠道和肝脏MPSS可以与循环共同的培养液流体偶联，而不会影响其功能。对双氯芬酸和氢化可的松在不同实验扰动下的PK进行了研究，结果表明该集成体系对定量PK研究具有较强的稳健性。对获得的数据进行基于机械模型的分析，可以得出与每个MPS中发生的PK过程相关的内在参数(例如，渗透性、代谢清除)。虽然这些过程并没有受到肠道-肝脏相互作用的实质性影响，但我们的结果表明，MPS之间的通讯可以起到调节作用(肝脏代谢上调)。我们预计，我们的综合方法结合了多细胞组织模型、多MPS平台和定量机制建模，将在临床前药物开发中具有广泛的适用性。
Investigation of the pharmacokinetics (PK) of a compound is of significant importance during the early stages of drug development and therefore several in vitro systems are routinely employed for this purpose. However, the need for more physiologically realistic in vitro models has recently fueled the emerging field of tissue engineered 3D cultures, also referred to as organs-on-chips, or microphysiological systems (MPSs). We have developed a novel fluidic platform that interconnects multiple MPSs, allowing PK studies in multi-organ in vitro systems along with the collection of high-content quantitative data. This platform was employed here to integrate a gut and a liver MPS together in continuous communication, and investigate simultaneously different PK processes taking place after oral drug administration in humans (e.g. intestinal permeability, hepatic metabolism). Measurement of tissue-specific phenotypic metrics indicated that gut and liver MPSs can be fluidically coupled with circulating common medium without compromising their functionality. The PK of diclofenac and hydrocortisone were investigated under different experimental perturbations and results illustrate the robustness of this integrated system for quantitative PK studies. Mechanistic model-based analysis of the obtained data allowed the derivation of the intrinsic parameters (e.g. permeability, metabolic clearance) associated with the PK processes taking place in each MPS. Although these processes were not substantially affected by the gut-liver interaction, our results indicate that inter-MPS communication can have a modulating effect (hepatic metabolism up-regulation). We envision that our integrative approach, which combines multi-cellular tissue models, multi-MPS platforms and quantitative mechanistic modeling, will have broad applicability in preclinical drug development.
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DOI：
10.1016/j.ejpb.2015.03.002
发表时间：
2015-09
期刊：
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V
影响因子：
--
作者：
Maschmeyer I;Hasenberg T;Jaenicke A;Lindner M;Lorenz AK;Zech J;Garbe LA;Sonntag F;Hayden P;Ayehunie S;Lauster R;Marx U;Materne EM
通讯作者：
Materne EM
在药物发现的边界，片上的器官。
DOI：
10.1038/nrd4539
发表时间：
2015-04
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Esch EW;Bahinski A;Huh D
通讯作者：
Huh D
影响因子：
38.3
作者：
Mahler, Gretchen J.;Esch, Mandy B.;Shuler, Michael L.
通讯作者：
Shuler, Michael L.
影响因子：
3.9
作者：
Long, Thomas J.;Cosgrove, Patrick A.;Griffith, Linda G.
通讯作者：
Griffith, Linda G.
用于细胞共培养和药物代谢模拟的集成微流体系统
影响因子：
3.9
作者：
Jie, Mingsha;Li, Hai-Fang;Lin, Jin-Ming
通讯作者：
Lin, Jin-Ming