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首页> 外文期刊>Alcohol >A physiologically based model for ethanol and acetaldehyde metabolism in human beings.
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A physiologically based model for ethanol and acetaldehyde metabolism in human beings.

机译：基于生理学的人类乙醇和乙醛代谢模型。

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Pharmacokinetic models for ethanol metabolism have contributed to the understanding of ethanol clearance in human beings. However, these models fail to account for ethanol's toxic metabolite, acetaldehyde. Acetaldehyde accumulation leads to signs and symptoms, such as cardiac arrhythmias, nausea, anxiety, and facial flushing. Nevertheless, it is difficult to determine the levels of acetaldehyde in the blood or other tissues because of artifactual formation and other technical issues. Therefore, we have constructed a promising physiologically based pharmacokinetic (PBPK) model, which is an excellent match for existing ethanol and acetaldehyde concentration-time data. The model consists of five compartments that exchange material: stomach, gastrointestinal tract, liver, central fluid, and muscle. All compartments except the liver are modeled as stirred reactors. The liver is modeled as a tubular flow reactor. We derived average enzymatic rate laws for alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH), determined kinetic parameters from the literature, and found best-fit parameters by minimizing the squared error between our profiles and the experimental data. The model's transient output correlates strongly with the experimentally observed results for healthy individuals and for those with reduced ALDH activity caused by a genetic deficiency of the primary acetaldehyde-metabolizing enzyme ALDH2. Furthermore, the model shows that the reverse reaction of acetaldehyde back into ethanol is essential and keeps acetaldehyde levels approximately 10-fold lower than if the reaction were irreversible.
机译：乙醇代谢的药代动力学模型有助于人们理解乙醇清除率。但是，这些模型无法说明乙醇的有毒代谢产物乙醛。乙醛积聚会导致体征和症状，例如心律不齐，恶心，焦虑和面部潮红。然而，由于人为形成和其他技术问题，难以确定血液或其他组织中乙醛的水平。因此，我们构建了一个有前途的基于生理的药代动力学（PBPK）模型，该模型与现有乙醇和乙醛浓度-时间数据非常匹配。该模型由五个交换物质的隔室组成：胃，胃肠道，肝脏，中央液体和肌肉。除肝脏外的所有隔室均以搅拌反应器为模型。肝脏被建模为管状流动反应器。我们推导了乙醇脱氢酶（ADH）和乙醛脱氢酶（ALDH）的平均酶速率定律，从文献中确定了动力学参数，并通过最小化我们的分布图和实验数据之间的平方误差找到了最佳拟合参数。该模型的瞬态输出与健康个体和主要乙醛代谢酶ALDH2基因缺陷导致ALDH活性降低的实验结果密切相关。此外，该模型表明，乙醛逆向转化为乙醇是必不可少的，它可以使乙醛水平比不可逆反应低约10倍。

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