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首页> 外文会议>International Conference on Bioinformatics and Computational Biology >Hepatocyte Organization Affects the Translation of Clearance from In Vitro to In Vivo
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Hepatocyte Organization Affects the Translation of Clearance from In Vitro to In Vivo

机译：肝细胞组织影响来自体外的清除的翻译

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An improved understanding of in vivo <==> in vitro changes is crucial in identifying and mitigating factors contributing to in vitro-in vivo extrapolation (IVIVE) inaccuracies in predicting the hepatic clearance of substances. We argue that a model mechanism-based virtual culture (vCulture) <==> virtual mouse (vMouse) (or vRat or vHuman) experiment approach can identify factors contributing to IVIVE disconnects. Doing so depends on having evidence that six Translational Requirements have been achieved. We cite evidence that the first four have been achieved. The fifth Requirement is that differences in measures of vCompound disposition between vCulture and vMouse are attributable solely to the micro-architectural, physiomimetic features, and uncertainties built into the vLiver and vMouse but are absent from the vCulture. The objective of this work is to first improve on a vCulture architecture used previously and then use results of virtual experiments to verify that its use enables the fifth Translational Requirement to be achieved. We employ two different idealized vCompounds, which map to highly permeable real compounds at the extreme ends of the intrinsic clearance spectrum. Virtual intrinsic clearance = Exposure rate per vHPC. At quasi-steady state, results for vCompound-1 are independent of the dosing rate. The average per-vHPC Exposure rates (taken over the whole vLiver in vMouse experiments) are the same (within the variance of the Experiments) as those in vCulture. However, they are location dependent within the vLiver. For vCompound-2, there are dosing rate differences and average per-vHPC Exposure rates within the vLiver are also location dependent. When we account for dosing rate differences, we see again that average per-vHPC Exposure rates averaged over the whole vLiver in vMouse experiments are the same as those in vCulture. Thus, the differences in per vHPC Exposure rate within the vLiver for both vCompounds are attributable solely to the micro-architectural and physiomimetic features built into the vLiver and vMouse but are absent from the vCulture. The results verify that the fifth Translational Requirement has been achieved.
机译：改进对体内的理解，在体外变化中的体外变化对于鉴定和减轻促进体内外推（常识）不准确性的因素来说至关重要，以预测物质的肝脏清除。我们认为基于模型机制的虚拟文化（VCulture）<==>虚拟鼠标（或vrat或Vhuman）实验方法可以识别有助于蠕动断开的因素。这样做取决于有证据表明已经实现了六种翻译要求。我们引用了证据表明前四个已经实现了。第五个要求是VCulture和VMOUSE之间VCompound配置措施的差异仅归因于vliver和vMouse内置的微观建筑，生理学特征和不确定性，而是从Vculture中缺席。这项工作的目的是首先改进先前使用的VCulture架构，然后使用虚拟实验的结果来验证其使用是否能够实现第五个转换要求。我们采用两种不同的理想化vCompounds，该vcompounds在内在清除谱的极端末端映射到高度可渗透的真实化合物。虚拟内在清除=每VHPC的暴露率。在准稳态，VCompound-1的结果与给药率无关。作为VCulture中的那些，平均每VHPC暴露率（覆盖在VMouse实验中的整个Vliver）是相同的（在实验的方差范围内）。但是，它们是vliver内的位置。对于vCompound-2，在vliver内的使用量差异和平均每VHPC曝光率也是依赖性的。当我们考虑用于计量率差异时，我们再次看到，在VMouse实验中的整个Vliver上平均平均每VHPC暴露率与VCulture中的整个Vliver相同。因此，对于VCompounds的VHPC曝光率在VHPC曝光率的差异仅归因于vliver和VMOUSE内置的微观建筑和生理学特征，而是从VCulture中缺席。结果验证了第五种翻译要求已经实现。

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