Quantitative Assessment of Population Variability in Hepatic Drug Metabolism Using a Perfused Three-Dimensional Human Liver Microphysiological System.
Quantitative Assessment of Population Variability in Hepatic Drug Metabolism Using a Perfused Three-Dimensional Human Liver Microphysiological System.
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DOI：
10.1124/jpet.116.237495
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发表时间：
2017-01
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;Kostrzewski T;Stokes CL;Griffith LG;Hughes DJ;Cirit M
在这项工作中，我们首先描述了在灌注的三维人肝脏微生理系统中培养的来自五种不同供体的冷冻保存的肝细胞在肝脏药物代谢中的群体变异性，然后展示了如何将所得数据与建模和模拟框架相结合，以完成体外-体内翻译。对于每个供体，测量了六种化合物（非那西丁、双氯芬酸、利多卡因、布洛芬、心得安和泼尼松龙）的代谢消耗谱，以及代谢物形成、90种代谢相关基因的mRNA水平和功能活力标记物[乳酸脱氢酶（LDH）释放、白蛋白和尿素生成]。药物消耗数据采用混合效应模型进行分析。在基因表达水平、药物代谢和其他测量的肝细胞功能方面，观察到大量的供体间差异。具体来说，非那西丁的内在代谢清除率的供体间变异性从24.1%到普萘洛尔的66.8%不等（以变异系数表示）。白蛋白、尿素、LDH和细胞色素P450 mRNA水平被确定为体外代谢清除率的重要预测因子。肝脏微生理系统的预测清除率与体内观察值相关。为利多卡因建立了一个基于人群生理的药代动力学模型，以说明体外输出到体内观察到的药代动力学变异性的转化。该模型的随机模拟成功地预测了观察到的临床浓度-时间分布和相关的人群变异性。这是首次在微生理系统背景下研究药物代谢的群体变异性，对在药物开发过程中使用这些系统具有重要意义。
In this work, we first describe the population variability in hepatic drug metabolism using cryopreserved hepatocytes from five different donors cultured in a perfused three-dimensional human liver microphysiological system, and then show how the resulting data can be integrated with a modeling and simulation framework to accomplish in vitro–in vivo translation. For each donor, metabolic depletion profiles of six compounds (phenacetin, diclofenac, lidocaine, ibuprofen, propranolol, and prednisolone) were measured, along with metabolite formation, mRNA levels of 90 metabolism-related genes, and markers of functional viability [lactate dehydrogenase (LDH) release, albumin, and urea production]. Drug depletion data were analyzed with mixed-effects modeling. Substantial interdonor variability was observed with respect to gene expression levels, drug metabolism, and other measured hepatocyte functions. Specifically, interdonor variability in intrinsic metabolic clearance ranged from 24.1% for phenacetin to 66.8% for propranolol (expressed as coefficient of variation). Albumin, urea, LDH, and cytochrome P450 mRNA levels were identified as significant predictors of in vitro metabolic clearance. Predicted clearance values from the liver microphysiological system were correlated with the observed in vivo values. A population physiologically based pharmacokinetic model was developed for lidocaine to illustrate the translation of the in vitro output to the observed pharmacokinetic variability in vivo. Stochastic simulations with this model successfully predicted the observed clinical concentration-time profiles and the associated population variability. This is the first study of population variability in drug metabolism in the context of a microphysiological system and has important implications for the use of these systems during the drug development process.
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影响因子：
4.5
作者：
Benet, Leslie Z.;Broccatelli, Fabio;Oprea, Tudor I.
通讯作者：
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影响因子：
3.5
作者：
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3.9
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通讯作者：
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作者：
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