Species Extrapolation of Life-Stage Physiologically-Based Pharmacokinetic (PBPK) Models to Investigate the Developmental Toxicology of Ethanol Using In vitro to In vivo (IVIVE) Methods
Species Extrapolation of Life-Stage Physiologically-Based Pharmacokinetic (PBPK) Models to Investigate the Developmental Toxicology of Ethanol Using In vitro to In vivo (IVIVE) Methods
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DOI：
10.1093/toxsci/kfu246
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发表时间：
2015-02-01
影响因子：
3.8
通讯作者：
El-Masri, Hisham
中科院分区：
文献类型：
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作者：
Martin, Sheppard A.;McLanahan, Eva D.;El-Masri, Hisham
为了提供体内动物研究的有用替代方案，异源化学物质的体外剂量反应评估必须使用在生物学上可信的范围内的介质和目标组织的浓度。测定这些浓度是一件复杂的事情，可以通过将体外基于生理的药代动力学(PBPK)模型应用到体内外推(IVIVE)范式来促进这一过程。我们使用乙醇(Etoh)作为模型化学物质来评估这一范例，乙醇是一种普遍存在的化学物质，具有确定的体内和体外胚胎毒性指标。已发表的一系列大鼠生命阶段PBPK模型被扩展到小鼠，产生的模拟充分预测了非怀孕和怀孕成年小鼠口服、腹膜和静脉途径的体内血乙醇浓度(BECs)。然后，这些模型被外推到未怀孕和怀孕的人身上，在2倍的范围内复制了BEC数据。然后使用啮齿动物模型进行体外静脉注射，以获得啮齿动物和全胚胎培养的胚胎毒性数据(神经管闭合缺陷、形态变化)。第二次IVE是在发育毒性敏感的关键窗口期间对孕妇进行的，例如最初6至8周(识别期前)或怀孕中后期，此时乙醇摄入与胎儿酒精谱障碍有关。结合来自人类胚胎干细胞研究的数据，导致了体外浓度与孕妇合理暴露范围之间的模型支持的联系。这项工作展示了使用多物种PBPK模型估计与体外胚胎毒性研究相关的体内组织浓度的好处和挑战。
To provide useful alternatives to in vivo animal studies, in vitro assays for dose-response assessments of xenobiotic chemicals must use concentrations in media and target tissues that are within biologically-plausible limits. Determining these concentrations is a complex matter, which can be facilitated by applying physiologically-based pharmacokinetic (PBPK) models in an in vitro to in vivo extrapolation (IVIVE) paradigm. We used ethanol (EtOH), a ubiquitous chemical with defined metrics for in vivo and in vitro embryotoxicity, as a model chemical to evaluate this paradigm. A published series of life-stage PBPK models for rats was extended to mice, yielding simulations that adequately predicted in vivo blood EtOH concentrations (BECs) from oral, intraperitoneal, and intravenous routes in nonpregnant and pregnant adult mice. The models were then extrapolated to nonpregnant and pregnant humans, replicating BEC data within a factor of two. The rodent models were then used to conduct IVIVEs for rodent and whole-embryo culture embryotoxicity data (neural tube closure defects, morphological changes). A second IVIVE was conducted for exposure scenarios in pregnant women during critical windows of susceptibility for developmental toxicity, such as the first 6-to-8 weeks (prerecognition period) or mid-to-late pregnancy period, when EtOH consumption is associated with fetal alcohol spectrum disorders. Incorporation of data from human embryonic stem cell studies led to a model-supported linkage of in vitro concentrations with plausible exposure ranges for pregnant women. This effort demonstrates benefits and challenges associated with use of multispecies PBPK models to estimate in vivo tissue concentrations associated with in vitro embryotoxicity studies.