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首页> 外文期刊>Risk analysis >Computational Modeling of Serum-Binding Proteins and Clearance in Extrapolations Across Life Stages and Species for Endocrine Active Compounds
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Computational Modeling of Serum-Binding Proteins and Clearance in Extrapolations Across Life Stages and Species for Endocrine Active Compounds

机译：血清结合蛋白的计算模型和内分泌活性化合物跨生命阶段和物种外推的清除率

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One measure of the potency of compounds that lead to the effects through ligand-dependent gene transcription is the relative affinity for the critical receptor. Endocrine active compounds that are presumed to act principally through binding to the estrogen receptor (e.g., estradiol, genistein, bisphenol A, and octylphenol) comprise one class of such compounds. For making simple comparisons, receptor-binding affinity has been equated to in vivo potency, which consequently defines the dose-response characteristics for the compound. Direct extrapolation of in vitro estimated affinities to the corresponding in vivo system and to specific species or life stages (e.g., neonatal, pregnancy) can be misleading. Accurate comparison of the potency of endocrine active compounds requires characterization of biochemical and pharmacoki-netic factors that affect their free concentration. Quantitative in vitro and in vivo models were developed for integrating pharmacokinetics factors (e.g., serum protein and receptor-binding affinities, clearance) that affect potency. Data for parameterizing these models for several estrogenic compounds were evaluated and the models exercised. While simulations of adult human or rat sera were generally successful, difficulties in describing early life stages were identified. Exogenous compounds were predicted to be largely ineffective at competing estradiol off serum-binding proteins, suggesting this was unlikely to be physiologically significant. Discrepancies were identified between relative potencies based upon modeling in vitro receptor-binding activity versus in vivo activity in the presence of clearance and serum-binding proteins. The examples illustrate the utility of this approach for integrating available experimental data from in vitro and in vivo studies to estimate the relative potency of these compounds.
机译：化合物通过配体依赖性基因转录产生影响的效力的一种量度是对关键受体的相对亲和力。推测主要通过与雌激素受体结合而起作用的内分泌活性化合物（例如，雌二醇，染料木黄酮，双酚A和辛基苯酚）构成一类这样的化合物。为了进行简单的比较，受体结合亲和力等同于体内效力，因此定义了该化合物的剂量反应特性。将体外估计的亲和力直接外推到相应的体内系统以及特定物种或生命阶段（例如新生儿，怀孕）可能会产生误导。准确比较内分泌活性化合物的功效需要表征影响其自由浓度的生化和药代动力学因素。开发了定量的体外和体内模型以整合影响功效的药代动力学因素（例如血清蛋白和受体结合亲和力，清除率）。评估了用于参数化这些模型中几种雌激素化合物的数据，并对模型进行了研究。虽然成人或大鼠血清的模拟通常是成功的，但在描述早期生命阶段时遇到了困难。预测外源化合物在与雌二醇竞争血清结合蛋白方面几乎无效，这表明这在生理上不太可能。根据清除和血清结合蛋白存在下体外受体结合活性与体内活性之间的关系模型，确定相对效力之间的差异。实施例说明了该方法用于整合来自体外和体内研究的可用实验数据以估计这些化合物的相对效力的效用。

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